Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them

ABSTRACT

The present invention relates to pharmaceutical formulations comprising at least one acid-labile proton pump inhibiting agent and at least one antacid, which have improved bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, safety, as well as other improved pharmacokinetic, pharmacodynamic, chemical and/or physical properties. The present invention is directed to methods, kits, combinations, and compositions for treating, preventing or reducing the risk of developing a gastrointestinal disorder or disease, or the symptoms associated with, or related to, a gastrointestinal disorder or disease in a subject in need thereof.

This application is a continuation-in-part of U.S. patent application Ser. No. 11/138,763, filed on May 25, 2005, which in turn claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 60/574,646, filed May 25, 2004 and U.S. Provisional Application No. 60/574,663, filed May 25, 2004, the contents of each of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical formulations in solid oral dosage form comprising at least one acid-labile proton pump inhibiting agent and at least one antacid, which have improved bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, safety, as well as other improved pharmacokinetic, pharmacodynamic, chemical and/or physical properties. Also described herein are pharmaceutical formulations comprising at least one proton pump inhibiting agent and about 5 mEq to about 11 mEq of antacid, which have similar bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, safety, as well as other improved pharmacokinetic, pharmacodynamic, chemical and/or physical properties to similar combinations comprising greater than 11 mEq of antacid.

The present invention is directed to methods, kits, combinations, and compositions for treating, preventing or reducing the risk of developing a gastrointestinal disorder or disease, or the symptoms associated with, or related to, a gastrointestinal disorder or disease in a subject in need thereof.

BACKGROUND OF THE INVENTION

Upon ingestion, most acid-labile pharmaceutical compounds must be protected from contact with acidic stomach secretions to maintain their pharmaceutical activity. To accomplish this, compositions with enteric-coatings have been designed to dissolve at a neutral pH to ensure that the drug is released in the proximal region of the small intestine (duodenum), rather than the acidic environment of the stomach. However, due to the pH-dependent attributes of these enteric-coated compositions and the uncertainty of gastric retention time, in-vivo performance as well as both inter- and intra-subject variability are all major set backs of using enteric-coated systems for the controlled release of a drug.

In addition, Phillips et al. has described non-enteric coated pharmaceutical compositions. These compositions, which allow for the immediate release of the pharmaceutically active ingredient into the stomach, involve the administration of one or more antacids with an acid labile pharmaceutical agent, such as a proton pump inhibitor. The antacid is thought to prevent substantial degradation of the acid labile pharmaceutical agent in the acidic environment of the stomach by raising the pH. See, e.g., U.S. Pat. Nos. 5,840,737 and 6,489,346.

A class of acid-labile pharmaceutical compounds that are administered as enteric-coated dosage forms are proton pump inhibiting agents. Exemplary proton pump inhibitors include:

omeprazole (Prilosec®), lansoprazole (Prevacid®), esomeprazole (Nexium®), rabeprazole (Aciphex®), pantoprazole (Protonix®), pariprazole, tenatoprazole, and leminoprazole. The drugs of this class suppress gastrointestinal acid secretion by the specific inhibition of the H⁺/K⁺-ATPase enzyme system (proton pump) at the secretory surface of the gastrointestinal parietal cell. Most proton pump inhibitors are susceptible to acid degradation and, as such, are rapidly destroyed as pH falls to an acidic level. Therefore, if the enteric-coating of these formulated products is disrupted (e.g., trituration to compound a liquid, or chewing the capsule or tablet) or the antacid fails to sufficiently neutralize the gastrointestinal pH, the drug will be exposed to degradation by the gastrointestinal acid in the stomach.

Omeprazole is one example of a proton pump inhibitor which is a substituted bicyclic aryl-imidazole, 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, that inhibits gastrointestinal acid secretion. U.S. Pat. No. 4,786,505 to Lovgren et al. teaches that a pharmaceutical oral solid dosage form of omeprazole must be protected from contact with acidic gastrointestinal juice by an enteric-coating to maintain its pharmaceutical activity and describes an enteric-coated omeprazole preparation containing one or more subcoats between the core material and the enteric-coating.

Proton pump inhibitors are typically prescribed for short-term treatment of active duodenal ulcers, gastrointestinal ulcers, gastro esophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive symptomatic GERD, and pathological hypersecretory conditions such as Zollinger Ellison syndrome. These above-listed conditions commonly arise in healthy or critically ill patients of all ages, and may be accompanied by significant upper gastrointestinal bleeding.

It is believed that omeprazole, lansoprazole and other proton pump inhibiting agents reduce gastrointestinal acid production by inhibiting H⁺/K⁺-ATPase of the parietal cell the final common pathway for gastrointestinal acid secretion. See, e.g., Fellenius et al., Substituted Benzimidazoles Inhibit Gastrointestinal Acid Secretion by Blocking H⁺/K⁺-ATPase, Nature, 290: 159-161 (1981); Wallmark et al., The Relationship Between Gastrointestinal Acid Secretion and Gastrointestinal H⁺/K⁺-ATPase Activity, J. Biol. Chem., 260: 13681-13684 (1985); and Fryklund et al., Function and Structure of Parietal Cells After H⁺/K⁺-ATPase Blockade, Am. J. Physiol., 254 (1988).

Proton pump inhibitors have the ability to act as weak bases that reach parietal cells from the blood and diffuse into the secretory canaliculi. There, the drugs become protonated and thereby trapped. The protonated compound can then rearrange to form a sulfenamide, which can covalently interact with sulfhydryl groups at critical sites in the extra cellular (luminal) domain of the membrane-spanning H⁺/K⁺-ATPase. See, e.g., Hardman et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, 907 (9th ed. 1996). As such, proton pump inhibitors are prodrugs that must be activated to be effective. The specificity of the effects of proton pump inhibiting agents is also dependent upon: (a) the selective distribution of H⁺/K⁺-ATPase; (b) the requirement for acidic conditions to catalyze generation of the reactive inhibitor; and (c) the trapping of the protonated drug and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme. See, e.g., Hardman et al.

SUMMARY OF THE INVENTION

The present invention is directed to pharmaceutical formulations in a solid oral dosage form comprising (a) at least one acid-labile proton pump inhibitor, and (b) at least one antacid sufficient to increase gastric pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid, wherein upon oral administration to a patient, a therapeutically effective amount of the proton pump inhibitor is delivered and T_(max) of the proton pump inhibitor is obtained within about 75 minutes after administration. In alternative embodiments, T_(max) of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In some embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.

In one embodiment, pharmaceutical formulations in a solid oral dosage form comprising (a) at least one acid-labile proton pump inhibitor; (b) a sufficient amount of sodium bicarbonate to increase gastric fluid pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid; and (c) less than about 3% of disintegrant, wherein upon oral administration to a patient a therapeutically effective amount of the proton pump inhibitor is delivered and T_(max) of the proton pump inhibitor is obtained within about 75 minutes after administration are described. In other embodiments, the pharmaceutical formulations comprise less than about 2% or less than about 1% of disintegrant. In alternative embodiments, T_(max) of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In some embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.

Stable pharmaceutical formulations in a solid oral dosage form comprising (a) at least one acid-labile proton pump inhibitor, and (b) at least one antacid in an amount sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid, wherein the pharmaceutical formulation does not comprise a binder; and wherein upon oral administration to a patient: a therapeutically effective amount of the proton pump inhibitor is delivered and T_(max) of the proton pump inhibitor is obtained within about 75 minutes after administration are also provided herein. In some embodiments, the antacid is present in an amount of greater than about 5 mEqs. In other embodiments, the antacid is present in an amount of about 5 mEq to about 30 mEq, or about 5 mEq to about 20 mEq, or about 8 mEq to about 15 mEq, or about 10 mEq to about 15 mEq. In still other embodiments, the antacid is present in an amount of about 5 mEq, or about 6 mEq, or about 7 mEq, or about 8 mEq, or about 9 mEq, or about 10 mEq, or about 11 mEq, or about 12 mEq, or about 13 mEq, or about 14 mEq, or about 15 mEq, or about 16 mEq, or about 17 mEq, or about 18 mEq, or about 19 mEq, or about 20 mEq, or about 22.5 mEq, or about 25 mEq, or about 27 mEq, or about 30 mEq, or about 35 mEq. In some embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.

Stable pharmaceutical formulations in a solid oral dosage form comprising (a) at least one acid-labile proton pump inhibitor, (b) at least about 5 mEq of antacid, wherein the antacid is a combination of at least two different antacids, and (c) between about 3% to about 11% of a disintegrant, wherein upon oral administration to a patient a therapeutically effective amount of the proton pump inhibitor is delivered and T_(max) of the proton pump inhibitor is obtained within about 75 minutes, are also provided herein. In some embodiments the pharmaceutical formulation comprises about 4% to about 8% disintegrant. In other embodiments, the pharmaceutical formulation comprises about 5% to about 7% disintegrant. In alternative embodiments, T_(max) of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In some embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral dosage form is a caplet.

Also provided herein are stable pharmaceutical formulations in a single capsule dosage form comprising (a) at least one acid-labile proton pump inhibitor, (b) about 5 to about 15 mEq of sodium bicarbonate, and (c) less than about 3% of a disintegrant, wherein upon oral administration to a patient a therapeutically effective amount of the proton pump inhibitor is delivered and T_(max) of the proton pump inhibitor is obtained within about 75 minutes. In some embodiments, the pharmaceutical formulation comprises about 8 mEq to about 15 mEq of sodium bicarbonate. In other embodiments, the pharmaceutical formulation comprises about 10 mEq to about 15 mEq of sodium bicarbonate. In yet other embodiments, the pharmaceutical formulation comprises about 13 mEq of sodium bicarbonate. In still other embodiments, T_(max) of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration.

Stable pharmaceutical formulations in a solid oral dosage form comprising (a) omeprazole or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof, (b) at least about 5 mEq of sodium bicarbonate, and (c) less than about 3% of a disintegrant, wherein the pharmaceutical formulation does not comprise a binder; and wherein upon oral administration to a patient a therapeutically effective amount of the proton pump inhibitor is delivered and T_(max) of the proton pump inhibitor is obtained within about 75 minutes after administration are also provided herein. In some embodiments, the pharmaceutical formulation comprises between about 5 mEq to about 20 mEq, or between about 5 mEq to about 15 mEq, or between about 10 mEq to about 15 mEq of sodium bicarbonate. In other embodiments, the pharmaceutical formulation comprises less than about 2% sodium bicarbonate. In yet other embodiments, T_(max) of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration. In some embodiments, the solid oral dosage form is a capsule. In other embodiments, the solid oral

dosage form is a caplet.

Also provided herein are stable pharmaceutical formulations in single capsule dosage form comprising (a) at least one acid-labile proton pump inhibitor, and (b) about 5 to about 30 mEq of antacid wherein the antacid is selected from magnesium hydroxide, magnesium oxide, sodium carbonate, sodium bicarbonate, and calcium carbonate, wherein upon oral administration to a patient: a therapeutically effective amount of the proton pump inhibitor is delivered; and T_(max) of the proton pump inhibitor is obtained within about 75 minutes. In other embodiments, T_(max) of the proton pump inhibitor is obtained within about 60 minutes, or within about 45 minutes, or within about 30 minutes after administration.

Also provided herein are pharmaceutical compositions in solid oral dosage forms wherein the wt-% of disintegrant is at least as great as the wt-% of binder. In some embodiments, the pharmaceutical formulation is substantially free of a binder. In other embodiments, the solid oral dosage form is a tablet (such as a caplet) and the binder is present in an amount of less than about 20 wt %, or less than about 10 wt-%, or less than about 5 wt-%. In other embodiments, the solid oral dosage form is a capsule and the binder is present in an amount of about 0 wt-% to about 5 wt-%.

The present invention provides a pharmaceutical composition comprising a proton pump inhibiting agent and about 5 mEq to about 11 mEq of antacid for oral administration and ingestion by a subject.

Pharmaceutical formulations are included that comprise (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein upon oral administration to a subject, the oral bioavailability of the proton pump inhibitor is at least 25% and the maximum serum concentration of the proton pump inhibitor is obtained within about 75 minutes after administration. In other embodiments, the maximum serum concentration is obtained within about 60 minutes, or within about 50 minutes, or within about 40 minutes, or within about 30 minutes, or within about 20 minutes after administration of the pharmaceutical formulation. In still other embodiments, the oral bioavailability of the proton pump inhibitor is about 25% to about 60%, or about 30% to about 50%, or at least about 30%, or at least about 35%, or at least about 40%.

Pharmaceutical formulations that comprise (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein the pharmaceutical formulation is bioequivalent to a pharmaceutical formulation comprising (a) at least one acid-labile proton pump inhibitor, and (b) greater than 11 mEq of antacid. In some embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±15% of the area under the serum concentration time curve for the proton pump inhibitor when an administered with greater than 11 mEq of antacid. In other embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±10% of the area under the serum concentration time curve for the proton pump inhibitor when an administered with greater than 11 mEq of antacid. In still other embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±5% of the area under the serum concentration time curve for the proton pump inhibitor when administered with greater than 11 mEq of antacid.

Pharmaceutical formulations that comprise (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein the pharmaceutical formulation is bioequivalent to a pharmaceutical formulation comprising (a) at least one acid-labile proton pump inhibitor, and (b) greater than 15 mEq of antacid. In some embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±15%, or within about ±10%, or within about ±5% of the area under the serum concentration time curve for the proton pump inhibitor when an administered with greater than 15 mEq of antacid.

Pharmaceutical formulations that comprise (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein the pharmaceutical formulation is bioequivalent to a pharmaceutical formulation comprising (a) at least one acid-labile proton pump inhibitor, and (b) greater than 20 mEq of antacid. In some embodiments, the area under the.serum concentration time curve for the proton pump inhibitor is within about ±15%, or within about ±10%, or within about ±5% of the area under the serum concentration time curve for the proton pump inhibitor when an administered with greater than 20 mEq of antacid.

Pharmaceutical formulations comprising (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid wherein the pharmaceutical formulation is bioequivalent to a proton pump inhibitor product. In some embodiments, the pharmaceutical formulation is bioequivalent to Priolosec®, Nexium®, Prevacid®, Protonic®, and Aciphex®. In other embodiments, the maximum concentration of the proton pump inhibitor for the pharmaceutical formulation is within about 80% and about 120% of the maximum concentration (Cmax) for the proton pump inhibitor product. In some embodiments, the maximum concentration of the proton pump inhibitor for the pharmaceutical formulation is within about 80% and about 120% of the maximum concentration (Cmax) for the proton pump inhibitor product when the pharmaceutical formulation and proton pump inhibitor product are administered to the same patient.

Pharmaceutical formulations comprising (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid are provided herein, wherein upon oral administration to a subject, the pharmaceutical composition has an area under the serum concentration time curve (AUC) for the proton pump inhibitor that is equivalent to an area under the serum concentration time curve (AUC) for the proton pump inhibitor when an enteric form of the proton pump inhibitor is delivered without antacid. In some embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±20% of the area under the serum concentration time curve for the proton pump inhibitor when an enteric form of the proton pump inhibitor is delivered without antacid. In still other embodiments, the area under the serum concentration time curve for the proton pump inhibitor is within about ±15%, or within about ±10%, or with about ±5% of the area under the serum concentration time curve for the proton pump inhibitor when an enteric form of the proton pump inhibitor is delivered without antacid.

Pharmaceutical formulations comprising (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid are provided herein, wherein a therapeutic dose of the proton pump inhibitor is delivered as a single capsule, tablet, or caplet.

A pharmaceutical formulations comprising (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein upon oral administration to a patient: a therapeutically effective amount of the proton pump inhibitor is delivered; the antacid increases the gastric pH to at least about 3.5 for no more than about 30 minutes measured by a simulated stomach model such as Fuchs kinetic in-vitro pH model; and the maximum concentration of the proton pump inhibitor is obtained within about 75 minutes are also provided herein. In some embodiments, the antacid increases the gastric pH to at least about 3.5 for less than about 30 minutes, or less than about 25 minutes, or less than about 20 minutes, or less than about 15 minutes, or less than about 10 minutes. In other embodiments, the maximum concentration of the proton pump inhibitor is obtained within about 60 minutes.

Pharmaceutical formulations comprising (a) at least one acid-labile proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid are provided herein, wherein the formulation comprises about 5 mgs to about 200 mgs of the proton pump inhibitor. In other embodiments, the pharmaceutical formulation comprises about 10 mgs, or about 20 mgs, or about 30 mgs, or about 40 mgs, or about 50 mgs, or about 60 mgs, or about 80 mgs, or about 120 mgs of the proton pump inhibitor. In yet other embodiments, the pharmaceutical formulation comprises about 5 mEq, or about 6 mEq, or about 7 mEq, or about 8 mEq, or about 9 mEq, or about 10 mEq, or about 11 mEq of antacid.

Compositions are provided such that an initial serum concentration of the proton pump inhibitor is greater than about 100 ng/ml at any time within about 30 minutes after administering the formulation. Initial serum concentration of the proton pump inhibitor can be greater than about 100 ng/ml at any time within about 15 minutes. Initial serum concentration of the proton pump inhibitor can be greater than about 200 ng/ml at any time within about 1 hour after administration, greater than about 300 ng/ml at any time within about 45 minutes after administration.

Compositions are provided such that a serum concentration of greater than about 100 ng/ml can be maintained from at least about 30 minutes to about 1 hour after administration of the composition. Compositions are provided such that a serum concentration of proton pump inhibitor greater than about 100 ng/ml can be maintained from at least about 15 minutes to about 30 minutes after administration. Compositions are provided such that a serum concentration of greater than about 100 ng/ml can be maintained from at least about 30 minutes to about 45 minutes after administration. Compositions are provided such that a serum concentration of greater than about 250 ng/ml can be maintained from at least about 30 minutes to about 1 hour after administration. Compositions are provided such that a serum concentration of greater than about 250 ng/ml can be maintained from at least about 30 minutes to about 45 minutes after administration. Compositions are provided such that a serum concentration of greater than about 250 ng/ml can be maintained from at least about 15 minutes to about 30 minutes after administration.

Compositions of the invention can be administered in an amount to maintain a serum concentration of the proton pump inhibitor greater than about 150 ng/ml from about 15 minutes to about 1 hour after administration. Compositions of the invention can be administered in an amount to maintain a serum concentration of the proton pump inhibitor greater than about 150 ng/ml from about 15 minutes to about 1.5 hours after administration. Compositions of the invention can be administered in an amount to maintain a serum concentration of the proton pump inhibitor greater than about 100 ng/ml from about 15 minutes to about 1.5 hours after administration. Compositions of the invention can be administered in an amount to maintain a serum concentration of the proton pump inhibitor greater than about 150 ng/ml from about 15 minutes to about 30 minutes after administration.

Compositions of the invention can be administered in an amount to achieve an initial serum concentration of the proton pump inhibitor greater than about 150 ng/ml at any time from about 5 minutes to about 30 minutes after administration. Compositions of the invention can be administered in an amount to achieve an initial serum concentration of the proton pump inhibitor greater than about 150 ng/ml at any time within about 30 minutes after administration.

Compositions are provided wherein, upon oral administration to the subject, the composition provides a pharmacokinetic profile such that at least about 50% of total area under serum concentration time curve (AUC) for the proton pump inhibitor occurs within about 2 hours after administration of a single dose of the composition to the subject. Compositions are provided wherein, upon oral administration to the subject, the area under the serum concentration time curve (AUC) for the proton pump inhibitor in the first 2 hours is at least about 60% of the total area. Compositions are provided wherein the area under the serum concentration time curve (AUC) for the proton pump inhibitor in the first 2 hours is at least about 70% of the total area.

Compositions are provided wherein at least about 50% of total area under the serum concentration time curve (AUC) for the proton pump inhibitor occurs within about 1.75 hours after administration of a single dose of the composition to the subject. Compositions are provided wherein at least about 50% of total area under the serum concentration time curve (AUC) for the proton pump inhibitor occurs within about 1.5 hours after administration of a single dose of the composition to the subject. Compositions are provided wherein at least about 50% of total area under the serum concentration time curve (AUC) for the proton pump inhibitor occurs within about 1 hour after administration of a single dose of the composition to the subject.

Compositions and methods are provided wherein, upon oral administration to the subject, the composition provides a pharmacokinetic profile such that the proton pump inhibitor reaches a maximum serum concentration within about 75 minutes after administration of a single dose of the pharmaceutical formulation. In yet other embodiments the maximum serum concentration is reached within about 60 minutes after administration, or within about 45 minutes after administration of the pharmaceutical formulation. In still other embodiments, the maximum serum concentration is reached within about 30 minutes after administration of the pharmaceutical formulation.

Methods are provided for treating a gastric acid related disorder including, but not limited to duodenal ulcer disease, gastric ulcer disease, gastroesophageal reflux disease, erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, pathological gastrointestinal hypersecretory disease, Zollinger Ellison syndrome, heartburn, esophageal disorder, and acid dyspepsia. Method are provided wherein the proton pump inhibitor treats an episode of gastric acid related disorder.

In some embodiments, the proton pump inhibitor is a substituted bicyclic aryl-imidazole. In other embodiments, the proton pump inhibitor is selected from the group consisting of omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, perprazole, ransoprazole, pariprazole, leminoprazole; or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof. In still other embodiments, the proton pump inhibitor is selected from lansoprazole, tenatoprazole, esomeprazole, rabeprazole and pantoprazole, or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof.

Pharmaceutical formulations of the present invention comprise, for example, about 5 mgs to about 200 mgs of a proton pump inhibitor. In various embodiments, the pharmaceutical formulation may comprise about 10 mgs, or about 15 mgs, or about 20 mgs, or about 40 mgs, or about 60 mgs, or about 120 mgs of the proton pump inhibitor.

In various embodiments of the present invention, the antacid is an alkaline metal salt or a Group IA metal selected from a bicarbonate salt of a Group IA metal, a carbonate salt of a Group IA metal. In other embodiments, the antacid can be, but is not limited to, an amino acid, an alkali metal salt of an amino acid, aluminum hydroxide, aluminum hydroxide/magnesium carbonate/calcium carbonate co-precipitate, aluminum magnesium hydroxide, aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate coprecipitate, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel, L-arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, trometamol, Effersoda® (a mixture of sodium bicarbonate and sodium carbonate) and mixtures thereof. In yet other embodiments, the antacid can be sodium bicarbonate, sodium carbonate, Effersoda®, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and mixtures thereof. In some embodiments, the composition is substantially free of sucralfate. In other embodiments, the composition does not contain an amino acid buffer. In still other embodiments, the composition is a combination of two or more antacids, wherein at least two of the antacids are not amino acids.

Pharmaceutical formulations of the present invention may comprise varying amounts of antacid. For example, in some embodiments, the pharmaceutical formulation comprises about 100 to 3000 mg of antacid. In other embodiments, the pharmaceutical formulation comprises about 400 to about 1300 mg of antacid. In still other embodiments the pharmaceutical formulation comprises about 5 mEq to about 30 mEq, or about 8 mEq to about 20 mEq, or about 10 mEq to about 15 mEq of antacid. In further embodiments, the pharmaceutical formulations comprise about 13 mEq of antacid.

Pharmaceutical formulations of the present invention may be in the form of a tablet, (including a suspension tablet, a chewable tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC) a lozenge, a sachet, a troche, pellets, granules, or an aerosol. In some embodiments, the pharmaceutical formulation is in the form of a powder for suspension. In other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a chewable tablet. Additionally, pharmaceutical formulations of the present invention may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules.

In various embodiments of the present invention, the proton pump inhibitor may be micro encapsulated with a material that enhances the shelf life of the pharmaceutical formulation. In some embodiments, the material that enhances the shelf life of the pharmaceutical formulation is selected from the group consisting of cellulose hydroxypropyl ethers; low-substituted hydroxypropyl ethers; cellulose hydroxypropyl methyl ethers; methylcellulose polymers; ethylcelluloses and mixtures thereof; polyvinyl alcohol; hydroxyethylcelluloses; carboxymethylcelluloses and salts of carboxymethylcelluloses; polyvinyl alcohol and polyethylene glycol co-polymers; monoglycerides; triglycerides; polyethylene glycols, modified food starch, acrylic polymers; mixtures of acrylic polymers with cellulose ethers; cellulose acetate phthalate; sepifilms, cyclodextrins; and mixtures thereof. In other embodiments, the material that enhances the shelf life of the pharmaceutical formulation further comprise an antioxidant, sodium bicarbonate, or a plasticizer.

In various embodiments, the pharmaceutical formulations of the present invention further comprise or more excipients selected from the group consisting of parietal cell activators, organic solvents, erosion facilitators, flavoring agents, sweetening agents, diffusion facilitators, antioxidants and carrier materials selected from binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, anti-adherents, and antifoaming agents.

DESCRIPTION OF THE FIGURES

FIG. 1 shows a comparison of buffer systems comprising various mixtures of NaHCO₃ and Mg(OH)₂.

FIG. 2 shows a comparison of buffer systems comprising various mixtures of NaHCO₃ and Mg(OH)₂.

FIG. 3 shows the particle size effect of magnesium hydroxide on in-vitro/in-vivo neutralization for immediate release capsule formulations SAN-10A, SAN-10B and SAN-10D.

FIG. 4 shows the particle size effect of magnesium hydroxide on the pharmacokinetics of various formulations.

FIG. 5 shows the binder effect on various pharmaceutical formulations.

FIG. 6 shows the capsule dissolution effect with 5% binder as compared to a powder for suspension.

FIG. 7 shows the pH study results of high/low Ac-Di-Sol (disintegrant).

FIG. 8 shows the pharmacokinetic study results of high/low Ac-Di-Sol (disintegrant) as compared to Prilosec.

FIG. 9 shows the pharmacokinetic profiles for six different pharmaceutical formulations.

FIG. 10 is a summary of exemplary formulations with the ANC present in the individual pharmaceutical formulations.

FIG. 11 is a summary of the pharmacokinetics of various formulations.

FIG. 12 shows the capsule stability of SAN-10E, SAN-10BB, and SAN-10B.

FIG. 13 compares the concentration/time curve for Prilosec® to the concentration/time curve of SAN-10K (10.5 mEq of Sodium Bicarbonate and 40 mg omeprazole).

FIG. 14 is a graph comparing the average pharmacokinetic release profiles of immediate release omeprazole chewable tablets (SAN-15A, SAN-15B and SAN-15C), capsules (SAN-10A, SAN-10B, SAN-10C, SAN-10E, SAN-10H, SAN-10BB), and a caplets (SAN-15D and SAN-15E) according to the present invention as compared to Priolosec® enteric coated omeprazole 40 mg. The compositions according to the present invention are all set forth in Table 13A, below.

FIG. 15 is a graph comparing the average pharmacokinetic release profiles of SAN-10BB (P9), SAN-10H (P8) and SAN-10B (P4) omeprazole capsules, 40 mg per dose. The formulations are described in detail in Example 13.

FIG. 16 is a graph comparing the Cmax and Tmax values for immediate release omeprazole powder, capsule, chew tab and caplet formulations according to the present invention with those of Prilosec® brand enteric coated omeprazole. The omeprazole powder is immediate release omeprazole powder for suspension, 20 or 40 mg micronized omeprazole and 1680 mg (20 mEq) of sodium bicarbonate, described in Example 16; the chewable tablets are 20 or 40 mg SAN-38 chewable tablets, as described herein; the capsules are SAN-7E (40 mg) or SAN-7F (20 mg) capsules as decribed in Examples 7, 14 and 15, below.

FIG. 17 is a graph comparing the average pharmacokinetic release profiles of immediate release omeprazole suspension (20 mg)(Example 16), chewable tablets (20 mg), capsule (20 mg)(Example 7F), and Prilosec® brand enteric coated omeprazole (20) mg from the human clinical trial described in Example 14B, Day 1.

FIG. 18 is a graph comparing the average pharmacokinetic release profiles of immediate release omeprazole suspension (40 mg)(Example 16), chewable tablets (40 mg), capsule (40 mg)(Example 7E), and Prilosec® enteric coated omeprazole (40 mg) from the human clinical trial described in Example 15B, Day 1.

FIG. 19 is a graph comparing the mean peak plasma concentration (Cmax) verses the time at which Cmax is observed (Tmax) for 20 mg and 40 mg immediate release chewable tablets, capsules (SAN-7F, SAN-7E, respectively), and immediate release omeprazole suspension according to the present invention and 20 and 40 mg Prilosec® enteric coated omeprazole. The data are from the human clinical trial in Examples 14B and 15 B, Day 1.

FIG. 20 is a graph comparing the average pharmacokinetic release profiles of immediate release omeprazole suspension (20 mg), chewable tablets (20 mg), capsule (20 mg) (SAN-7F) according to the present invention with Prilosec (20 mg) from the human clinical trial in Example 14B, Day 7.

FIG. 21 is a graph comparing the average pharmacokinetic release profiles of immediate release omeprazole suspension (40 mg), chewable tablets (40 mg), capsule (40 mg) (SAN-7E) according to the present invention with Prilosec® brand enteric coated omeprazole (40 mg) from the human clinical trial in Example 15B, Day 7.

FIG. 22 is a graph comparing the mean peak plasma concentration (Cmax) verses the time at which Cmax is observed (Tmax) for immediate release omeprazole chewable tablets, capsules, and suspension according to the present invention (20 and 40 mg) and Prilosec® brand enteric coated omeprazole (20 and 40 mg) from the human clinical trial set forth in 14B, 15B Day 7.

FIG. 23 is a graph comparing the Cmax versus Tmax of immediate release omeprazole chewable tablets, capsules, and suspension according to the present invention and Prilosec® brand enteric coated omeprazole. The data for both 20 mg and 40 mg doses are from the clinical trial set forth in Examples 14B, 15B, Days 1 and 7.

FIG. 24 is a flow chart depicting Manufacturing Process of immediate release capsules according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods, kits, combinations, and compositions for treating a condition or disorder where treatment with an acid labile proton pump inhibitor is indicated. Also provided are methods, kits, combinations, and compositions for treating, preventing or reducing the risk of developing a gastrointestinal disorder or disease, or the symptoms associated with, or related to a gastrointestinal disorder or disease in a subject in need thereof.

While the present invention may be embodied in many different forms, several specific embodiments are discussed herein with the understanding that the present disclosure is to be considered only as an exemplification of the principles of the invention, and it is not intended to limit the invention to the embodiments illustrated. For example, where the present invention is illustrated herein with particular reference to omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, periprazole, ransoprazole, pariprazole, or leminoprazole, it will be understood that any other proton pump inhibiting agent, if desired, can be substituted in whole or in part for such agents in the methods, kits, combinations, and compositions herein described.

To more readily facilitate an understanding of the invention and its preferred embodiments, the meanings of terms used herein will become apparent from the context of this specification in view of common usage of various terms and the explicit definitions of other terms provided in the glossary below or in the ensuing description.

Glossary

As used herein, the terms “comprising,” “including,” and “such as” are used in their open, non-limiting sense.

The term “about” is used synonymously with the term “approximately.” As one of ordinary skill in the art would understand, the exact boundary of “about” will depend on the component of the composition. Illustratively, the use of the term “about” indicates that values slightly outside the cited values, i.e., plus or minus 0.1% to 10%, which are also effective and safe.

The phrase “acid-labile pharmaceutical agent” refers to any pharmacologically active drug subject to acid catalyzed degradation.

“Anti-adherents,” “glidants,” or “anti-adhesion” agents prevent components of the formulation from aggregating or sticking and improve flow characteristics of a material. Such compounds include, e.g., colloidal silicon dioxide such as Cab-o-sil®; tribasic calcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin, and micronized amorphous silicon dioxide (Syloid®) and the like.

“Antifoaming agents” reduce foaming during processing which can result in coagulation of aqueous dispersions, bubbles in the finished film, or generally impair processing. Exemplary anti-foaming agents include silicon emulsions or sorbitan sesquoleate.

“Antioxidants” include, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

“Binders” impart cohesive qualities and include, e.g., alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

“Bioavailability” refers to the extent to which an active moiety, e.g., drug, prodrug, or metabolite, is absorbed into the general circulation and becomes available at the site of drug action in the body. Thus, a proton pump inhibitor administered through IV is 100% bioavailable. “Oral bioavailability” refers to the extent to which the proton pump inhibitor (or other active moiety) is absorbed into the general circulation and becomes available at the site of drug action in the body when the pharmaceutical composition is taken orally.

“Bioequivalence” or “bioequivalent” means that the area under the serum concentration time curve (AUC) and the peak serum concentration (C_(max)) are each within 80% and 120%.

“Carrier materials” include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with the proton pump inhibitor and the release profile properties of the desired dosage form. Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. “Pharmaceutically compatible carrier materials” may comprise, e.g., acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999).

“Character notes” include, e.g., aromatics, basis tastes, and feeling factors. The intensity of the character note can be scaled from 0-none, 1-slight, 2-moderate, or 3-strong.

A “derivative” is a compound that is produced from another compound of similar structure by the replacement of substitution of an atom, molecule or group by another suitable atom, molecule or group. For example, one or more hydrogen atom of a compound may be substituted by one or more alkyl, acyl, amino, hydroxyl, halo, haloalkyl, aryl, heteroaryl, cycloaolkyl, heterocycloallcyl, or heteroalkyl group to produce a derivative of that compound.

“Diffusion facilitators” and “dispersing agents” include materials that control the diffusion of an aqueous fluid through a coating. Exemplary diffusion facilitators/dispersing agents include, e.g., hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG and the like. Combinations of one or more erosion facilitator with one or more diffusion facilitator can also be used in the present invention.

“Diluents” increase bulk of the composition to facilitate compression. Such compounds include e.g., lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose such as Avicel®; dibasic calcium phosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calcium phosphate; anhydrous lactose; spray-dried lactose; pregelatinzed starch; compressible sugar, such as Di-Pac® (Amstar); mannitol; hydroxypropylmethylcellulose; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; dextrates; hydrolyzed cereal solids; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; mannitol; sodium chloride; inositol; bentonite; and the like.

The term “disintegrate” includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid.

“Disintegration agents” facilitate the breakup or disintegration of a substance. Examples of disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®; a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and SolkaFloc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as crospovidone; a cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; a clay such as Veegum® HV (magnesium aluminum silicate); a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation-exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination starch; and the like.

“Drug absorption” or “absorption” refers to the process of movement from the site of administration of a drug toward the systemic circulation, e.g., into the bloodstream of a subject.

An “enteric coating” is a substance that remains substantially intact in the stomach but dissolves and releases the drug once the small intestine is reached. Generally, the enteric coating comprises a polymeric material that prevents release in the low pH environment of the stomach but that ionizes at a slightly higher pH, typically a pH of 4 or 5, and thus dissolves sufficiently in the small intestines to gradually release the active agent therein.

The “enteric form of the proton pump inhibitor” is intended to mean that some or most of the proton pump inhibitor has been enterically coated to ensure that at least some of the drug is released in the proximal region of the small intestine (duodenum), rather than the acidic environment of the stomach.

“Erosion facilitators” include materials that control the erosion of a particular material in gastrointestinal fluid. Erosion facilitators are generally known to those of ordinary skill in the art. Exemplary erosion facilitators include, e.g., hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

“Filling agents” include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose; dextrates; dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

“Flavoring agents” or “sweeteners” useful in the pharmaceutical compositions of the present invention include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

“Gastrointestinal fluid” is the fluid of stomach secretions of a subject or the saliva of a subject after oral administration of a composition of the present invention, or the equivalent thereof. An “equivalent of stomach secretion” includes, e.g., an in vitro fluid having similar content and/or pH as stomach secretions such as a 1% sodium dodecyl sulfate solution or 0.1N HCl solution in water.

“Half-life” refers to the time required for the plasma drug concentration or the amount in the body to decrease by 50% from its maximum concentration.

“Lubricants” are compounds that prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, e.g., stearic acid; calcium hydroxide; talc; sodium stearyl fumerate; a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex®); higher fatty acids and their alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, sodium oleate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid™, Carb-O-Sil®, a starch such as corn starch, silicone oil, a surfactant, and the like.

A “measurable serum concentration” or “measurable plasma concentration” describes the blood serum or blood plasma concentration, typically measured in mg, μg, or ng of therapeutic agent per ml, dl, or l of blood serum, of a therapeutic agent that is absorbed into the bloodstream after administration. One of ordinary skill in the art would be able to measure the serum concentration or plasma concentration of a proton pump inhibitor or a prokinetic agent. See, e.g., Gonzalez H. et al., J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci., vol. 780, pp 459-65, (Nov. 25, 2002).

“Parietal cell activators” or “activators” stimulate the parietal cells and enhance the pharmaceutical activity of the proton pump inhibitor. Parietal cell activators include, e.g., chocolate; alkaline substances such as sodium bicarbonate; calcium such as calcium carbonate, calcium gluconate, calcium hydroxide, calcium acetate and calcium glycerophosphate; peppermint oil; spearmint oil; coffee; tea and colas (even if decaffeinated); caffeine; theophylline; theobromine; amino acids (particularly aromatic amino acids such as phenylalanine and tryptophan); and combinations thereof.

“Pharmacodynamics” refers to the factors which determine the biologic response observed relative to the concentration of drug at a site of action.

“Pharmacokinetics” refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at a site of action.

“Plasma concentration” refers to the concentration of a substance in blood plasma or blood serum of a subject. It is understood that the plasma concentration of a therapeutic agent may vary many-fold between subjects, due to variability with respect to metabolism of therapeutic agents. In accordance with one aspect of the present invention, the plasma concentration of a proton pump inhibitors and/or prokinetic agent may vary from subject to subject. Likewise, values such as maximum plasma concentration (C_(max)) or time to reach maximum serum concentration (T_(max)), or area under the serum concentration time curve (AUC) may vary from subject to subject. Due to this variability, the amount necessary to constitute “a therapeutically effective amount” of proton pump inhibitor, prokinetic agent, or other therapeutic agent, may vary from subject to subject. It is understood that when mean plasma concentrations are disclosed for a population of subjects, these mean values may include substantial variation.

“Plasticizers” are compounds used to soften the microencapsulation material or film coatings to make them less brittle. Suitable plasticizers include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin.

“Prevent” or “prevention” when used in the context of a gastric acid related disorder means no gastrointestinal disorder or disease development if none had occurred, or no further gastrointestinal disorder or disease development if there had already been development of the gastrointestinal disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the gastrointestinal disorder or disease.

A “prodrug” refers to a drug or compound in which the pharmacological action results from conversion by metabolic processes within the body. Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present on the prodrug which renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. The design of prodrugs to date has been to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent. See, e.g., Fedorak et al., Am. J. Physiology, 269:G210-218 (1995); McLoed et al., Gastroenterol., 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

“Proton pump inhibitor product” refers to a product sold on the market. Proton pump inhibitor products include, for example, Priolosec®, Nexium®, Prevacid®, Protonic®, and Aciphex®.

“Serum concentration” refers to the concentration of a substance such as a therapeutic agent, in blood plasma or blood serum of a subject. It is understood that the serum concentration of a therapeutic agent may vary many-fold between subjects, due to variability with respect to metabolism of therapeutic agents. In accordance with one aspect of the present invention, the serum concentration of a proton pump inhibitors and/or prokinetic agent may vary from subject to subject. Likewise, values such as maximum serum concentration (C_(max)) or time to reach maximum serum concentration (T_(max)), or total area under the serum concentration time curve (AUC) may vary from subject to subject. Due to this variability, the amount necessary to constitute “a therapeutically effective amount” of proton pump inhibitor, prokinetic agent, or other therapeutic agent, may vary from subject to subject. It is understood that when mean serum concentrations are disclosed for a population of subjects, these mean values may include substantial variation.

“Solubilizers” include compounds such as citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, sodium carbonate and the like.

“Stabilizers” include compounds such as any antioxidation agents, buffers, acids, and the like.

“Suspending agents” or “thickening agents” include compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30; polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400; sodium carboxymethylcellulose; methylcellulose; hydroxy-propylmethylcellulose; polysorbate-80; hydroxyethylcellulose; sodium alginate; gums, such as, e.g., gum tragacanth and gum acacia; guar gum; xanthans, including xanthan gum; sugars; cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose; polysorbate-80; sodium alginate; polyethoxylated sorbitan monolaurate; polyethoxylated sorbitan monolaurate; povidone and the like.

“Surfactants” include compounds such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF); and the like.

A “therapeutically effective amount” or “effective amount” is that amount of a pharmaceutical agent to achieve a pharmacological effect. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a proton pump inhibitor is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. For example, an effective amount of a proton pump inhibitor refers to an amount of proton pump inhibitor that reduces acid secretion, or raises gastrointestinal fluid pH, or reduces gastrointestinal bleeding, or reduces the need for blood transfusion, or improves survival rate, or provides for a more rapid recovery from a gastric acid related disorder. The effective amount of a pharmaceutical agent will be selected by those skilled in the art depending on the particular patient and the disease level. It is understood that “an effect amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of therapeutic agents such as proton pump inhibitors and/or prokinetic agents, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.

“Total intensity of aroma” is the overall immediate impression of the strength of the aroma and includes both aromatics and nose feel sensations.

“Total intensity of flavor” is the overall immediate impression of the strength of the flavor including aromatics, basic tastes and mouth feel sensations.

“Treat” or “treatment” as used in the context of a gastric acid related disorder refers to any treatment of a disorder or disease associated with a gastrointestinal disorder, such as preventing the disorder or disease from occurring in a subject which may be predisposed to the disorder or disease, but has not yet been diagnosed as having the disorder or disease; inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder. Thus, as used herein, the term “treat” is used synonymously with the term “prevent.”

“Wetting agents” include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, and the like.

Proton Pump Inhibitors

The terms “proton pump inhibitor,” “PPI,” and “proton pump inhibiting agent” can be used interchangeably to describe any acid labile pharmaceutical agent possessing pharmacological activity as an inhibitor of H+/K+-ATPase. A proton pump inhibitor may, if desired, be in the form of free base, free acid, salt, ester, hydrate, anhydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or the like, provided that the free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, or any other pharmacologically suitable derivative is therapeutically active.

In various embodiments, the proton pump inhibitor can be a substituted bicyclic aryl-imidazole, wherein the aryl group can be, e.g., a pyridine, a phenyl, or a pyrimidine group and is attached to the 4- and 5-positions of the imidazole ring. Proton pump inhibitors comprising a substituted bicyclic aryl-imidazoles include, but are not limited to, omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, habeprazole, perprazole, tenatoprazole, ransoprazole, pariprazole, leminoprazole, or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative thereof. See, e.g., The Merck Index, Merck & Co. Rahway, N.J. (2001).

Other proton pump inhibitors include but are not limited to: soraprazan (Altana); ilaprazole (U.S. Pat. No. 5,703,097) (Il-Yang); AZD-0865 (AstraZeneca); YH-1885 (PCT Publication WO 96/05177) (SB-641257) (2-pyrimidinamine, 4-(3,4-dihydro-1-methyl-2(1H)-isoquinolinyl)-N-(4-fluorophenyl)-5,6-dimethyl-monohydrochloride)(YuHan); BY-112 (Altana); SPI-447 (Imidazo(1,2-a)thieno(3,2-c)pyridin-3-amine,5-methyl-2-(2-methyl-3-thienyl) (Shinnippon); 3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano(2,3-c)-imidazo(1,2-a)pyridine (PCT Publication WO 95/27714) (AstraZeneca); Pharmaprojects No. 4950 (3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano(2,3-c)-imidazo(1,2-a)pyridine) (AstraZeneca, ceased) WO 95/27714; Pharmaprojects No. 4891 (EP 700899) (Aventis); Pharmaprojects No. 4697 (PCT Publication WO 95/32959) (AstraZeneca); H-335/25 (AstraZeneca); T-330 (Saitama 335) (Pharmacological Research Lab); Pharmaprojects No. 3177 (Roche); BY-574 (Altana); Pharmaprojects No. 2870 (Pfizer); AU-1421 (EP 264883) (Merck); AU-2064 (Merck); AY-28200 (Wyeth); Pharmaprojects No. 2126 (Aventis); WY-26769 (Wyeth); pumaprazole (PCT Publication WO 96/05199) (Altana); YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publication WO 97/32854) (Dainippon); BY-686 (Altana); YM-020 (Yamanouchi); GYKI-34655 (Ivax); FPL-65372 (Aventis); Pharmaprojects No. 3264 (EP 509974) (AstraZeneca); nepaprazole (Toa Eiyo); HN-11203 (Nycomed Pharma); OPC-22575; pumilacidin A (BMS); saviprazole (EP 234485) (Aventis); SKandF-95601 (GSK, discontinued); Pharmaprojects No. 2522 (EP 204215) (Pfizer); S-3337 (Aventis); RS-13232A (Roche); AU-1363 (Merck); SKandF-96067 (EP 259174) (Altana); SUN 8176 (Daiichi Phama); Ro-18-5362 (Roche); ufiprazole (EP 74341) (AstraZeneca); and Bay-p-1455 (Bayer); or a free base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of these compounds.

Still other proton pump inhibitors contemplated by the present invention include those described in the following U.S. Pat. Nos: 4,628,098; 4,689,333; 4,786,505; 4,853,230; 4,965,269; 5,021,433; 5,026,560; 5,045,321; 5,093,132; 5,430,042; 5,433,959; 5,576,025; 5,639,478; 5,703,110; 5,705,517; 5,708,017; 5,731,006; 5,824,339; 5,855,914; 5,879,708; 5,948,773; 6,017,560; 6,123,962; 6,187,340; 6,296,875; 6,319,904; 6,328,994; 4,255,431; 4,508,905; 4,636,499; 4,738,974; 5,690,960; 5,714,504; 5,753,265; 5,817,338; 6,093,734; 6,013,281; 6,136,344; 6,183,776; 6,328,994; 6,479,075; 6,559,167.

Other substituted bicyclic aryl-imidazole compounds as well as their salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, and derivatives may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry. See, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992); Leonard et al., Advanced Practical Organic Chemistry (1992); Howarth et al., Core Organic Chemistry (1998); and Weisermel et al., Industrial Organic Chemistry (2002).

“Pharmaceutically acceptable salts,” or “salts,” include, e.g., the salt of a proton pump inhibitor prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acids.

In one embodiment, acid addition salts are prepared from the free base using conventional methodology involving reaction of the free base with a suitable acid. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

In other embodiments, an acid addition salt is reconverted to the free base by treatment with a suitable base. In a further embodiment, the acid addition salts of the proton pump inhibitors are halide salts, which are prepared using hydrochloric or hydrobromic acids. In still other embodiments, the basic salts are alkali metal salts, e.g., sodium salt.

Salt forms of proton pump inhibiting agents include, but are not limited to: a sodium salt form such as esomeprazole sodium, omeprazole sodium, rabeprazole sodium, pantoprazole sodium; or a magnesium salt form such as esomeprazole magnesium or omeprazole magnesium, described in U.S. Pat. No. 5,900,424; a calcium salt form; or a potassium salt form such as the potassium salt of esomeprazole, described in U.S. patent application Ser. No. 02/0198239 and U.S. Pat. No. 6,511,996. Other salts of esomeprazole are described in U.S. Pat. No. 4,738,974 and U.S. Pat. No. 6,369,085. Salt forms of pantoprazole and lansoprazole are discussed in U.S. Pat. Nos. 4,758,579 and 4,628,098, respectively.

In one embodiment, preparation of esters involves fictionalization of hydroxyl and/or carboxyl groups which may be present within the molecular structure of the drug. In one embodiment, the esters are acyl-substituted derivatives of free alcohol groups, e.g., moieties derived from carboxylic acids of the formula RCOOR₁ where R₁ is a lower alkyl group. Esters can be reconverted to the free acids, if desired, by using conventional procedures such as hydrogenolysis or hydrolysis.

“Amides” may be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with an amine group such, as ammonia or a lower alkyl amine.

“Tautomers” of substituted bicyclic aryl-imidazoles include, e.g., tautomers of omeprazole such as those described in U.S. Pat. Nos.: 6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020; 6,326,384; 6,369,087; and 6,444,689; and U.S. Patent Publication No. 02/0156103.

An exemplary “isomer” of a substituted bicyclic aryl-imidazole is the isomer of omeprazole including but not limited to isomers described in: Oishi et al., Acta Cryst. (1989), C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S. Patent Publication No. 02/0156284; and PCT Publication No. WO 02/085889.

Exemplary “polymorphs” include, but are not limited to, those described in PCT Publication No. WO 92/08716, and U.S. Pat. Nos. 4,045,563; 4,182,766; 4,508,905; 4,628,098; 4,636,499; 4,689,333; 4,758,579; 4,783,974; 4,786,505; 4,808,596; 4,853,230; 5,026,560; 5,013,743; 5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093,342; 5,433,959; 5,464,632; 5,536,735; 5,576,025; 5,599,794; 5,629,305; 5,639,478; 5,690,960; 5,703,110; 5,705,517; 5,714,504; 5,731,006; 5,879,708; 5,900,424; 5,948,773; 5,997,903; 6,017,560; 6,123,962; 6,147,103; 6,150,380; 6,166,213; 6,191,148; 5,187,340; 6,268,385; 6,262,086; 6,262,085; 6,296,875; 6,316,020; 6,328,994; 6,326,384; 6,369,085; 6,369,087; 6,380,234; 6,428,810; 6,444,689; and 6,462,0577.

Micronized Proton Pump Inhibitor

Particle size of the proton pump inhibitor can affect the solid dosage form in numerous ways. Since decreased particle size increases in surface area (S), the particle size reduction provides an increase in the rate of dissolution (dM/dt) as expressed in the Noyes-Whitney equation below:

dM/dt=dS/h(Cs−C)

M=mass of drug dissolved; t=time; D=diffusion coefficient of drug; S=effective surface area of drug particles; H=stationary layer thickness; Cs=concentration of solution at saturation; and C=concentration of solution at time t.

Because omeprazole, as well as other proton pump inhibitors, has poor water solubility, to aid the rapid absorption of the drug product, various embodiments of the present invention use micronized proton pump inhibitor is used in the drug product formulation.

In various embodiments of the present invention, the proton pump inhibitor is micronized. In some embodiments, the average particle size of at least about 90% the micronized proton pump inhibitor is less than about 40 μm, or less than about 35 μm, or less than about 30 μm, or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, or less than about 10 μm. In other embodiments, at least 80% of the micronized proton pump inhibitor has an average particle size of less than about 40 μm, or less than about 35 μm, or less than about 30 μm, or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, or less than about 19 μm. In still other embodiments, at least 70% of the micronized proton pump inhibitor has an average particle size of less than about 40 μm, or less than about 35 μm, or less than about 30 μm, or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, or less than about 10 μm.

Compositions are provided wherein the micronized proton pump inhibitor is of a size which allows greater than 75% of the proton pump inhibitor to be released within about 1 hour, or within about 50 minutes, or within about 40 minutes, or within about 30 minutes, or within about 20 minutes, or within about 10 minutes, or within about 5 minutes of dissolution testing. In another embodiment of the invention, the micronized proton pump inhibitor is of a size which allows greater than 90% of the proton pump inhibitor to be released within about 1 hour, or within about 50 minutes, or within about 40 minutes, or within about 30 minutes, or within about 20 minutes, or within about 10 minutes, or within about 5 minutes of dissolution testing. See U.S. patent application Ser. No. 10/893,092, filed Jul. 16, 2004, which claims priority to U.S. Provisional Application No. 60/488,324 filed Jul. 18, 2003, both of which are incorporated by reference in their entirety.

Particle Size of Ingredients

The particle size of the proton pump inhibitor, antacid and excipients is an important factor which can effect bioavailability, blend uniformity, segregation, and flow properties. In general, smaller particle sizes of a drug increases the bioabsorption rate of the drug with substantially poor water solubility by increasing the surface area. The particle size of the drug and excipients can also affect the suspension properties of the pharmaceutical formulation. For example, smaller particles are less likely to settle and therefore form better suspensions.

In various embodiments, the average particle size of the dry powder (which can be administered directly, as a powder for suspension, or used in a solid dosage form) is less than about 500 microns in diameter, or less than about 450 microns in diameter, or less than about 400 microns in diameter, or less than about 350 microns in diameter, or less than about 300 microns in diameter, or less than about 250 microns in diameter, or less than about 200 microns in diameter, or less than about 150 microns in diameter, or less than about 100 microns in diameter, or less than about 75 microns in diameter, or less than about 50 microns in diameter, or less than about 25 microns in diameter, or less than about 15 microns in diameter. In other embodiments, the average particle size of the aggregates is between about 25 microns in diameter to about 300 microns in diameter. In still other embodiments, the average particle size of the aggregates is between about 25 microns in diameter to about 150 microns in diameter. And, in still further embodiments, the average particle size of the aggregates is between about 25 microns in diameter to about 100 microns in diameter. The term “average particle size” is intended to describe the average diameter of the particles and/or agglomerates used in the pharmaceutical formulation.

In another embodiment, the average particle size of the insoluble excipients is between about 5 μm to about 500 μm, or less than about 400 μm, or less than about 300 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 90 μm, or less than about 80 μm, or less than about 70 μm, or less than about 60 μm, or less than about 50 μm, or less than about 40 μm, or less than about 30 μm, or less than about 25 μm, or less than about 20 μm, or less than about 15 μm, or less than about 10 μm, or less than about 5 μm.

In other embodiments of the present invention, at least about 80% of the particles have a particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 500 μm. In another embodiment, at least about 85% of the dry powder particles have a particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 50 μm. In still other embodiments of the present invention, at least about 90% of the dry powder particles have a particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 50 μm. In yet another embodiment, at least about 95% of the dry powder particles have a particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm, or less than about 50 μm.

In other embodiments, the average particle size of the insoluble material is between about 5 μm to about 250 μm in diameter. In other embodiments, the average particle size of the insoluble excipients is between about 5 μm to about 100 μm, or between about 5 μm to about 80 μm, or between about 5 μm to about 50 μm in diameter.

In another embodiment, the particle size of other excipients is chosen to be about the same as the particle size of the antacid. In yet another embodiment, the particle size of the insoluable excipients is chosen to be about the same as the particle size of the proton pump inhibitor.

Several factors can be considered in choosing both the proper excipient and its quantity. For example, the excipient should be pharmaceutically acceptable. Also, in some examples, rapid dissolution and neutralization of gastric acid to maintain the gastric pH at about 6.5 for at least one hour. The excipients which will be in contact with the proton pump inhibitor, if any, should also be chemically compatible with the proton pump inhibitor. “Chemically compatible” is intended to mean that the material does not lead to more than 10% degradation of the proton pump inhibitor when stored at room temperature for at least about 1 year.

Parietal cell activators are administered in an amount sufficient to produce the desired stimulatory effect without causing untoward side effects to patients. In one embodiment, the parietal cell activator is administered in an amount of about 5 mg to about 2.5 grams per 20 mg dose of the proton pump inhibitor.

Antacids

The pharmaceutical composition of the invention comprises one or more antacids. A class of antacids useful in the present invention include, but are not limited to, antacids possessing pharmacological activity as a base. In one embodiment, the antacid, when formulated or delivered with an proton pump inhibiting agent, functions to substantially prevent or inhibit the acid degradation of the proton pump inhibitor by gastrointestinal fluid for a period of time, e.g., for a period of time sufficient to preserve the bioavailability of the proton pump inhibitor administered. The antacid can be delivered before, during and/or after delivery of the proton pump inhibitor. In one aspect of the present invention, the antacid includes a salt of a Group IA metal (alkali metal), including, e.g., a bicarbonate salt of a Group IA metal, a carbonate salt of a Group IA metal; an alkaline earth metal antacid (Group IIA metal); an aluminum antacid; a calcium antacid; or a magnesium antacid.

Other antacids suitable for the present invention include, e.g., alkali metal (a Group IA metal including, but not limited to, lithium, sodium, potassium, rubidium, cesium, and francium) or alkaline earth metal (Group IIA metal including, but not limited to, beryllium, magnesium, calcium, strontium, barium, radium) carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrate, succinates and the like, such as sodium or potassium phosphate, citrate, borate, acetate, bicarbonate and carbonate.

In various embodiments, an antacid includes an amino acid, an alkali metal salt of an amino acid, aluminum hydroxide, aluminum hydroxide/magnesium carbonate/calcium carbonate co-precipitate, aluminum magnesium hydroxide, aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate coprecipitate, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel, L-arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, Effersoda® (mixture of sodium bicarbonate and sodium carbonate), synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, and trometamol. (See, e.g., lists provided in The Merck Index, Merck & Co. Rahway, N.J. (2001)). Certain proteins or protein hydrolysates that rapidly neutralize acids can serve as antacids in the present invention. Combinations of the above mentioned antacids may also be used in the pharmaceutical compositions described herein.

The antacids useful in the present invention also include antacids or combinations of antacids that interact with HCl (or other acids in the environment of interest) faster than the proton pump inhibitor interacts with the same acids. When placed in a liquid phase, such as water, these antacids produce and maintain a pH greater than the pKa of the proton pump inhibitor.

In various embodiments, the antacid is selected from sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, and mixtures thereof.

The antacids useful in the present invention also include antacids or combinations of antacids that interact with HCl (or other acids in the environment of interest) faster than the proton pump inhibitor interacts with the same acids. When placed in a liquid phase, such as water, these antacids produce and maintain a pH greater than the pKa of the proton pump inhibitor.

In various embodiments, the antacid is selected from sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and mixtures thereof. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount greater than about 5 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount greater than about 7 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount greater than about 10 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount greater than about 15 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount greater than about 20 mEq of antacid.

In another embodiment, the antacid comprises sodium bicarbonate in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton pump inhibitor. In yet another embodiment, the antacid comprises a mixture of sodium bicarbonate and magnesium hydroxide, wherein the sodium bicarbonate and magnesium hydroxide are each present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton pump inhibitor. In still another embodiment, the antacid comprises a mixture of sodium bicarbonate, calcium carbonate, and magnesium hydroxide, wherein the sodium bicarbonate, calcium carbonate, and magnesium hydroxide are each present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg of the proton pump inhibitor.

In various other embodiments of the present invention, the antacid is present in an amount of about 0.1 mEq/mg to about 5 mEq/mg of the proton pump inhibitor, or about 0.5 mEq/mg to about 3 mEq/mg of the proton pump inhibitor, or about 0.6 mEq/mg to about 2.5 mEq/mg of the proton pump inhibitor, or about 0.7 mEq/mg to about 2.0 mEq/mg of the proton pump inhibitor, or about 0.8 mEq/mg to about 1.8 mEq/mg of the proton pump inhibitor, or about 1.0 mEq/mg to about 1.5 mEq/mg of the proton pump inhibitor, or at least 0.5 mEq/mg of the proton pump inhibitor.

In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an from about 5 to about 50 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount from about 5 to about 40 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount from about 10 to about 30 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount from about 10 to about 20 mEq of antacid. In other embodiments, the antacid is present in the pharmaceutical formulations of the present invention in an amount from about 5 to about 15 mEq of antacid.

In another embodiment, the antacid is present in the pharmaceutical formulations of the present invention in an amount of about 0.1 mEq to about 15 mEq/mg of proton pump inhibitor, or about 0.1 mEq/mg of proton pump inhibitor, or about 0.5 mEq/mg of proton pump inhibitor, or about 1 mEq/mg of proton pump inhibitor, or about 2 mEq/mg of proton pump inhibitor, or about 2.5 mEq/mg of proton pump inhibitor, or about 3 mEq/mg of proton pump inhibitor, or about 3.5 mEq/mg of proton pump inhibitor, or about 4 mEq/mg of proton pump inhibitor, or about 4.5 mEq/mg of proton pump inhibitor, or about 5 mEq/mg of proton pump inhibitor, or about 6 mEq/mg of proton pump inhibitor, or about 7 mEq/mg of proton pump inhibitor, or about 8 mEq/mg of proton pump inhibitor, or about 9 mEq/mg of proton pump inhibitor, or about 10 mEq/mg of proton pump inhibitor, or about 11 mEq/mg of proton pump inhibitor, or about 12 mEq/mg of proton pump inhibitor, or about 13 mEq/mg of proton pump inhibitor, or about 14 mEq/mg of proton pump inhibitor, or about 15 mEq/mg of proton pump inhibitor.

In one embodiment, the antacid is present in the pharmaceutical formulations of the present invention in an amount of about 1 mEq to about 160 mEq per dose, or about 1 mEq, or about 5 mEq, or about 10 mEq, or about 15 mEq, or about 20 mEq, or about 25 mEq, or about 30 mEq, or about 35 mEq, or about 40 mEq, or about 45 mEq, or about 50 mEq, or about 60 mEq, or about 70 mEq, or about 80 mEq, or about 90 mEq, or about 100 mEq, or about 110 mEq, or about 120 mEq, or about 130 mEq, or about 140 mEq, or about 150 mEq, or about 160 mEq per dose.

In another embodiment, the antacid is present in an amount of more than about 5 times, or more than about 10 times, or more than about 20 times, or more than about 30 times, or more than about 40 times, or more than about 50 times, or more than about 60 times, or more than about 70 times, or more than about 80 times, or more than about 90 times, or more than about 100 times the amount of the proton pump inhibiting agent on a weight to weight basis in the composition.

In another embodiment, the amount of antacid present in the pharmaceutical formulation is between 200 and 3500 mg. In other embodiments, the amount of antacid present in the pharmaceutical formulation is about 200 mgs, or about 300 mgs, or about 400 mgs, or about 500 mgs, or about 600 mgs, or about 700 mgs, or about 800 mgs, or about 900 mgs, or about 1000 mgs, or about 1100 mgs, or about 1200 mgs, or about 1300 mgs, or about 1400 mgs, or about 1500 mgs, or about 1600 mgs, or about 1700 mgs, or about 1800 mgs, or about 1900 mgs, or about 2000 mgs, or about 2100 mgs, or about 2200 mgs, or about 2300 mgs, or about 2400 mgs, or about 2500 mgs, or about 2600 mgs, or about 2700 mgs, or about 2800 mgs, or about 2900 mgs, or about 3000 mgs, or about 3200 mgs, or about 3500 mgs.

In some embodiments, if the at least one buffering agent is a combination of two or more buffering agents, the combination comprises at least two non-amino acid buffering agents, wherein the combination of at least two non-amino acid buffering agents comprises substantially no aluminum hydroxide-sodium bicarbonate co-precipitate. In other embodiments, if the pharmaceutical composition comprises an amino acid buffering agent, the total amount of buffering agent present in the pharmaceutical composition is less than about 5 mEq, or less than about 4 mEq, or less than about 3 mEq. The phrase “amino acid buffering agent” as used herein includes amino acids, amino acid salts, and amino acid alkali salts. including: glycine, alanine, threonine, isoleucine, valine, phenylalanine, glutamic acid, asparagininic acid, lysine, aluminum glycinate and/or lysine glutamic acid salt, glycine hydrochloride, L-alanine, DL-alanine, L-threonine, DL-threonine, L-isoleucine, L-valine, L-phenylalanine, L-glutamic acid, L-glutamic acid hydrochloride, L-glutamic acid sodium salt, L-asparaginic acid, L-asparaginic acid sodium salt, L-lysine and L-lysine-L-glutamic acid salt. The term “non-amino acid buffering agent” herein includes buffering agents as defined hereinabove but does not include amino acid buffering agents.

In other embodiments, the pharmaceutical composition comprises substantially no or no poly[phosphoryl/sulfon]-ated carbohydrate and is in the form of a solid dosage unit. In still another related embodiment, if such a composition comprises a poly[phosphoryl/sulfon]-ated carbohydrate (e.g. sucralfate or sucrose octasulfate), the weight ratio of poly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is less than 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05). Alternatively, the poly[phosphoryl/sulfon]-ated carbohydrate is present in the composition, if at all, in an amount less than 50 mg, less than 25 mg, less than 10 mg or less than 5 mg.

Also provided herein are pharmaceutical formulations comprising at least one soluble antacid. For example, in one embodiment, the antacid is sodium bicarbonate and is present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton pump inhibitor. In another embodiment, the antacid is a mixture of sodium bicarbonate and magnesium hydroxide, wherein the sodium bicarbonate and magnesium hydroxide are each present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton pump inhibitor. The term “soluble antacid” as used herein refers to an antacid that has a solubility of at least 500 mg/mL, or 300 mg/mL, or 200 mg/mL, or 100 mL/mL in the gastrointestinal fluid.

In some embodiments of the present invention, the antacid is a specific particle size. For example, the average particle size of the antacid may be no greater than 20 μm, or no greater than 30 μm, or no greater than 40 μm, or no greater than 50 μm, or no greater than 60 μm, or no greater than 70 μm, or no greater than 80 μm, or no greater than 90 μm or no greater than 100 μm in diameter. In various embodiments, at least about 70% of the antacid is no greater than 20 μm, or no greater than 30 μm, or no greater than 40 μm, or no greater than 50 μm, or no greater than 60 μm, or no greater than 70 μm, or no greater than 80 μm, or no greater than 90 μm or no greater than 100 μm in diameter. In other embodiments, at least about 85% of the antacid is no greater than 20 μm, or no greater than 30 μm, or no greater than 40 μm, or no greater than 50 μm, or no greater than 60 μm, or no greater than 70 μm, or no greater than 80 μm, or no greater than 90 μm or no greater than 100 μm in diameter.

Particle size of the buffer, especially that an insoluble buffer can affect the onset of in-vivo neutralization of the stomach acid. Since decreased particle size increases in surface area, the particle size reduction provides an increase in the rate of acid neutralization, leading to superior protection of PPI from gastric acid degradation. On the other hand, extremely fine particle size of buffer will result in the powder mixture that is difficult to manufacture in commercial scale due to their poor flow and difficulties in processing (i.e., compression and encapsulation).

In various embodiments of the present invention, the antacid is micronized. In some embodiments, particle size of at least 90% of antacid (D₉₀) is less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm. In other embodiments, at least 75% of the antacid (D₇₅) has particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm. In still other embodiments, at least 50% of the antacid (D₅₀) has particle size of less than about 300 μm, or less than about 250 μm, or less than about 200 μm, or less than about 150 μm, or less than about 100 μm.

Spray dried antacid can also facilitate the speed of neutralization by fast reacting with acid upon contact. Sprayed dried antacid typically has spherical particle shape which aids with achieving homogeneous blend during manufacturing process. In one embodiment the antacid is spray dried with at least 15% of coating material such as maltodextrin or starch. In still other embodiment the antacid is spray dried with at least 10% of coating material such as maltodextrin or starch. Yet another embodiment the antacid is spray dried with at least 15% of coating material such as maltodextrin or starch.

Kinetic Stomach Model

The acid neutralizing capacity and pH profile of various antacid combinations can be evaluated by using an in-vitro stomach model. Several of these simulated dynamic models are known in the art. See, e.g., Smyth et al., Correlation of In-Vivo Methodology for Evaluation of Antacids, J. Pharm. Sci. Vol. 65, 1045 (1976); Hobert, Fordham et al., In-Vivo Evaluation of Liquid Antacids, New England Journal of Med. 288, 923 (1973); Johnson et al., The Chemical Testing of Antacids, Gut 5, 585 (1964); Clain et al., In-Vitro Neutralizing Capacity of Commercially Available Antacid Mixtures and Their Role in the Treatment of Peptic Ulcer, S. Afr. Med. J., 57, 158 (1980); Rossett et al., In-Vitro Evaluation of Efficacy of More Frequently Used Antacids with Particular Attention to Tablets, Gastroentrology, 26, 490; Decktor et al., Comparative Effects of Liquid Antacids on Esophageal and Gastric pH in Patients with Heartburn, Am. J. of Therapeutics, 2, 481 (1995); Charles Fuchs, Antacids: Their Function, Formulation and Evaluation, Drug and Cosmetic Industry, 49, 692; Stewart M. Beekman, Preparation and Properties of New Gastric Antacids I, Aluminium Hydroxide-Magnesium Carbonate Dried Gels, J. Am. Pharm. Assoc., 49, 191 (1960). For example, a modified Fuch's model where the continuous influx of 0.5 mEq of acid is added to initial 5.0 mEq of acid to simulate a fasting state of stomach can be used with the present invention.

In various embodiments of the present invention, the antacid increases the gastric pH to at least about 3.5 for no more than about 90 minutes as measured by a simulated stomach model such as Fuch's kinetic in-vitro pH model. In other embodiments, the antacid increases the pH to at least about 3.5 for no more than about 60 minutes. In still other embodiments, the antacid increases the pH to at least about 3.5 for no more than 45 minutes. Depending on the buffer system used (i.e., type of antacid and amount) some embodiments of the present invention, the antacid increases the gastric pH to at least about 3.5 for no more than about 30 minutes as measured by a simulated stomach model such as Fuchs' kinetic in-vitro pH model. In other embodiments, the antacid increases the gastric pH to at least about 3.5 for less than about 25 minutes as measured by a simulated stomach model such as Fuch's kinetic in-vitro pH model. In yet other embodiments, the antacid increases the gastric pH to at least about 3.5 for less than about 20 minutes, or less than about 15 minutes, or less than about 10 minutes as measured by a stimulated stomach model such as Fuch's kinetic in-vitro pH model. In each of these embodiments, the antacid protects at least some of the proton pump inhibitor and a therapeutically effective amount of the proton pump inhibitor is delivered to the subject.

In each of these embodiments, the antacid protects at least some of the proton pump inhibitor and a therapeutically effective amount of the proton pump inhibitor is delivered to the subject.

Disintegrants

Most PPIs are sparingly soluble in water and therefore exhibit a correlation of disintegration time to bioavailability. Thus, it is important to optimize the disintegration time in order to enhance in vivo dissolution of the drug. In order to release the active ingredient from a solid dosage form matrix as efficiently as possible, disintegrant is often used in the formulation, especially when the dosage forms are compressed with binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Starch is the oldest disintegrants and 5-15% level is suggested (Remington, 20th Ed, p 862). Super disintegrants such as Ac-di-Sol or Crospovidones are effective at lower levels (2-4%).

Ac-Di-Sol is effective in both direct compression and wet granulation formulations. The amount of Ac-Di-Sol used in direct compression tableting may vary with typical usage levels between 1 and 3 percent. When added to granulations, generally the same percent is used as with a direct compression formulation. It is often added to both the wet mass and the dried granulations before compression. As with direct compression, the use level typically ranges from 1 to 3 percent with half of the material added to the wet mass and half added to the running powder. This promotes disintegration of both the granules and the tablet.

The amount of Ac-Di-Sol used in capsule formulations generally ranges from 4-6 percent. Reduced interparticle contact within a capsule facilitates the need for elevated levels of disintegrant. Capsules filled on automatic dosater types of equipment, as opposed to semi-automatic or hand-filled machines, are more dense and have a harder structure due to the greater compressional forces needed to form the plug and successfully transfer it into the gelatin shell. Greater plug hardness results in greater effectiveness of Ac-Di-Sol.

Solid Oral Dosage Forms

In some embodiments of the present invention, the pharmaceutical formulation has greater than about 1 wt-% of a disintegrant. In various embodiments of the present invention, the pharmaceutical formulations have between about 1 wt-% to about 11 wt-% or between about 1 wt-% to about 8 wt-%, or about 1 wt-% to about 6 wt-%, or about 1 wt-% to about 4 wt-%, of a disintegrant. In some embodiments the disintegrant is Ac-Di-Sol. In other embodiments the disintegrant is sodium starch glycolated such as Promogel® or Explotab®. In still other embodiments, the pharmaceutical formulations have between about 2 wt-% to about 8 wt-% disintegrant, or between about 2 wt-% to about 6 wt-%, or between about 2 wt-% to about 4 wt-%. In yet other embodiments, the pharmaceutical formulations have greater than about 2 wt-% disintegrant.

Because sodium bicarbonate has effervescent characteristic when mixed with acid such as gastric fluid, some embodiments of the pharmaceutical formulations of the present invention can comprise at least about 400 mgs of sodium bicarbonate and greater than about 1 wt-% of a disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2 wt-% disintegrant, or about 3 wt-% disintegrant, or about 4 wt-% disintegrant. In yet other embodiments, the pharmaceutical formulation comprises less than 8 wt-% disintegrant. In other embodiments, the pharmaceutical formulations have less than about 5 wt-% disintegrant, or less than about 4 wt-% disintegrant, or less than about 3 wt-% disintegrant, or less than about 2 wt-% disintegrant, or less than about 1 wt-% disintegrant. In other embodiments, the sodium bicarbonate helps facilitate the disintegration of the capsule product.

Because sodium bicarbonate has effervescent characteristic when mixed with acid such as gastric fluid, some embodiments of the pharmaceutical formulations of the present invention can comprise at least about 200 mgs of sodium bicarbonate and greater than about 1 wt-% of a disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2 wt-% disintegrant, or about 3 wt-% disintegrant, or about 4 wt-% disintegrant. In yet other embodiments, the pharmaceutical formulation comprises less than 8 wt-% disintegrant. In other embodiments, the pharmaceutical formulations have less than about 5 wt-% disintegrant, or less than about 4 wt-% disintegrant, or less than about 3 wt-% disintegrant, or less than about 2 wt-% disintegrant, or less than about 1 wt-% disintegrant. In other embodiments, the sodium bicarbonate helps facilitate the disintegration of the capsule product.

In some embodiments of the present invention, the wt-% of disintegrant can be decreased and the amount of sodium bicarbonate increased to achieve the desired bioavailability of the proton pump inhibitor. In other embodiments, the wt-% of disintegrant can be increased and the amount of sodium bicarbonate decreased to achieve the desired bioavailability of the proton pump inhibitor.

Binders

Binders impart a cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into a hard sell capsules and for tablet formulation, they ensure the tablet remaining intact after compression. Materials commonly used as binders include starch gelatin, and sugars such as sucrose, glucose, dextrose, molasses, and lactose. The quantity of binder used influences the characteristics of the dosage form and/or manufacturing processes. For example, dosator type encapsulators (e.g. Zanasi machine) normally requires the filling material to be mechanically strong plugs whereas dosing disc type encapsulators (e.g., HK machine) do not require the same degree of high plug breaking force. In general, binder level of 1-10% are used in powder-filled hard gel capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of 2-25% in tablet formulations is common.

In some embodiments of the present invention, the wt-% of the disintegrant is at least equivalent to the wt-% of the binder. For example, formulations of the present invention may comprise about 5 wt-% of disintegrant and about 2 wt-% of a binder or about 3 wt-% of a disintegrant and about 3 wt-% of a binder. In other embodiments, the solid oral dosage form does not comprise a binder. In some embodiments, the solid oral dosage form comprises significantly more disintegrant than binder. For example, the binder may be present in an amount of less than 2 wt-% while the disintegrant is present in an amount of greater than 5 wt-%. In other embodiments, the binder and disintegrant are present in the formulation in substantially the same amount. For example, the binder may be present in an amount of about 2 wt-% and the disintegrant may be present in an amount of about 3 wt-%.

Microencapsulation

In accordance with one aspect of the present invention, compositions may include microencapsulation of the proton pump inhibitor or the antacid, in order to enhance the shelf life of the composition and/or enhance the taste of the pharmaceutical composition. See U.S. application Ser. No. 10/893,203, filed Jul. 16, 2004, which claims priority to U.S. Provisional Application No. 60/488,321 filed Jul. 18, 2003, both of which are incorporated by reference in their entirety.

Materials useful for enhancing the shelf life and/or masking the taste of the pharmaceutical compositions of the present invention include materials compatible with the proton pump inhibitor of the pharmaceutical compositions which sufficiently isolate the proton pump inhibitor from other non-compatible excipients. Materials compatible with the proton pump inhibitors of the present invention are those that enhance the shelf life of the proton pump inhibitor, i.e., by slowing or stopping degradation of the proton pump inhibitor.

Exemplary microencapsulation materials useful for enhancing the shelf life of pharmaceutical compositions comprising a proton pump inhibitor include, but are not limited to: hydroxypropyl cellulose ethers (HPC) such as Klucel® or Nisso HPC; low-substituted hydroxypropyl cellulose ethers (L-HPC); hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel®-A and Metolose®; Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel®, Aqualon®-EC, Surelease®; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol®; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon®-CMC; polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR®; monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® RD100, and Eudragit® E100; cellulose acetate phthalate; sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins; and mixtures of these materials.

In various embodiments, an antacid such as sodium bicarbonate or sodium carbonate is incorporated into the microencapsulation material. In other embodiments, an antioxidant such as BHT is incorporated into the microencapsulation material. In still other embodiments, plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulating material useful for enhancing the shelf life of the pharmaceutical compositions is from the USP or the National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is methocel.

In further embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, parietal cell activators, erosion facilitators, diffusion facilitators, anti-adherents, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

According to one aspect of the invention, some of the proton pump inhibitor is coated. The coating may be, for example, a gastric resistant coating such as an enteric coating (See, e.g, WO 91/16895 and WO 91/16886), a controlled-release coating, an enzymatic-controlled coating, a film coating, a sustained-release coating, an immediate-release coating, or a delayed-release coating. According to another aspect of the invention, the coating may be useful for enhancing the stability of the pharmaceutical compositions of the present invention.

In addition to microencapsulating the proton pump inhibitors with a material as described herein, the pharmaceutical compositions of the present invention may also comprise one or more flavoring agents. In some embodiments, one or more flavoring agents are mixed with the taste-masking material prior to microencapsulating the proton pump inhibitor and/or antacid. In other embodiments, the flavoring agent is mixed with non-compatible excipients during the formulation process and is therefore not in contact with the proton pump inhibitor and/or antacid, and not part of the microencapsulation material.

“Flavoring agents” or “sweeteners” useful in the pharmaceutical compositions of the present invention include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. In other embodiments, sodium chloride is incorporated into the pharmaceutical composition. Based on the proton pump inhibitor, antacid, and excipients, as well as the amounts of each one, one of skill in the art would be able to determine the best combination of flavors to provide the optimally flavored product for consumer demand and compliance. See, e.g., Roy et al., Modifying Bitterness: Mechanism, Ingredients, and Applications (1997).

Methods of Microencapsulation

The proton pump inhibitor and/or antacid may be microencapsulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath. In addition to these, several chemical techniques, e.g., complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used.

The spinning disk method allows for: 1) an increased production rate due to higher feed rates and use of higher solids loading in feed solution, 2) the production of more spherical particles, 3) the production of a more even coating, and 4) limited clogging of the spray nozzle during the process.

Spray drying is often more readily available for scale-up. In various embodiments, the material used in the spray-dry encapsulation process is emulsified or dispersed into the core material in a concentrated form, e.g., 10-60% solids. The microencapsulation material is, in one embodiment, emulsified until about 1 to 3 μm droplets are obtained. Once a dispersion of proton pump inhibitor and encapsulation material are obtained, the emulsion is fed as droplets into the heated chamber of the spray drier. In some embodiments, the droplets are sprayed into the chamber or spun off a rotating disk. The microspheres are then dried in the heated chamber and fall to the bottom of the spray drying chamber where they are harvested.

In some embodiments of the present invention, the microspheres have irregular geometries. In other embodiments, the microspheres are aggregates of smaller particles.

In various embodiments, the proton pump inhibitor and/or antacid are present in the microspheres in an amount greater than 1%, greater than 2.5%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90% greater than 95% or greater than 98% weight percent of the proton pump inhibitor to the microencapsulation material used to enhance the stability of the pharmaceutical composition or the taste-masking material.

Stability

A pharmaceutical formulation of the present invention is stable if, e.g., the proton pump inhibitor has less than about 0.5% degradation after one month of storage at room temperature, or less than about 1% degradation after one month at room temperature, or less than about 1.5% degradation after one month of storage at room temperature, or less than about 2% degradation after one month storage at room temperature, or less than about 2.5% degradation after one month of storage at room temperature, or less than about 3% degradation after one month of storage at room temperature.

In other embodiments, a pharmaceutical formulation of the present invention may have stable if the pharmaceutical formulation contains less than about 5% total impurities after about 3 years of storage, or after about 2.5 years of storage, or about 2 years of storage, or about 1.5 years of storage, or about 1 year of storage, or after 11 months of storage, or after 10 months of storage, or after 9 months of storage, or after 8 months of storage, or after 7 months of storage, or after 6 months of storage, or after 5 months of storage, or after 4 months of storage, or after 3 months of storage, or after 2 months of storage, or after 1 month of storage.

In further embodiments, pharmaceutical formulations of the present invention may contain microencapsulated omeprazole and have enhanced shelf life stability if the pharmaceutical formulation contains less degradation of the proton pump inhibitor than proton pump inhibitor in the same formulation which is not microencapsulated, or “bare”. For example, if bare proton pump inhibitor in the pharmaceutical formulation degrades at room temperature by more than about 2% after one month of storage and the microencapsulated material degrades at room temperature by less than about 2% after one month of storage, then the proton pump inhibitor has been microencapsulated with a compatible material that enhances the shelf life of the pharmaceutical formulation.

Dosage

The proton pump inhibiting agent is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, and other factors known to medical practitioners. In human therapy, it is important to provide a dosage form that delivers the required therapeutic amount of the therapeutic agent in vivo, and renders therapeutic agent bioavailable in a rapid manner. In addition to the dosage forms described herein, the dosage forms described by Phillips et al. in U.S. Pat. Nos. 5,840,737, 6,489,346, 6,699,885 and 6,645,988 are incorporated herein by reference.

The percent of intact drug that is absorbed into the bloodstream is not narrowly critical, as long as a therapeutically effective amount, e.g., a gastrointestinal-disorder-effective amount of a proton pump inhibiting agent, is absorbed following administration of the pharmaceutical composition to a subject. Gastrointestinal-disorder-effective amounts may be found in U.S. Pat. No. 5,622,719. It is understood that the amount of proton pump inhibiting agent and/or antacid that is administered to a subject is dependent on a number of factors, e.g., the sex, general health, diet, and/or body weight of the subject.

Illustratively, administration of a substituted bicyclic aryl-imidazole to a young child or a small animal, such as a dog, a relatively low amount of the proton pump inhibitor, e.g., about 1 mg to about 30 mg, will often provide blood serum concentrations consistent with therapeutic effectiveness. Where the subject is an adult human or a large animal, such as a horse, achievement of a therapeutically effective blood serum concentration will require larger dosage units, e.g., about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 80 mg, or about 120 mg dose for an adult human, or about 150 mg, or about 200 mg, or about 400 mg, or about 800 mg, or about 1000 mg dose, or about 1500 mg dose, or about 2000 mg dose, or about 2500 mg dose, or about 3000 mg dose or about 3200 mg dose or about 3500 mg dose for an adult horse.

In various other embodiments of the present invention, the amount of proton pump inhibitor administered to a subject is, e.g., about 0.5-2 mg/Kg of body weight, or about 0.5 mg/Kg of body weight, or about 1 mg/Kg of body weight, or about 1.5 mg/Kg of body weight, or about 2 mg/Kg of body weight.

Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for subject administration. In terms of treatment protocols, it should be appreciated that the dosage to be administered will depend on several factors, including the particular agent that is administered, the route chosen for administration, and the condition of the particular subject.

In various embodiments, unit dosage forms for humans contain about 1 mg to about 120 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg, or about 110 mg, or about 120 mg of a proton pump inhibitor.

In a further embodiment of the present invention, the pharmaceutical composition is administered in an amount to achieve a measurable serum concentration of a non-acid degraded proton pump inhibiting agent greater than about 100 ng/ml within about 30 minutes after administration of the pharmaceutical composition. In another embodiment of the present invention, the pharmaceutical composition is administered to the subject in an amount to achieve a measurable serum concentration of a non-acid degraded or non-acid reacted proton pump inhibiting agent greater than about 100 ng/ml within about 15 minutes after administration of the pharmaceutical composition. In yet another embodiment, the pharmaceutical composition is administered to the subject in an amount to achieve a measurable serum concentration of a non-acid degraded or non-acid reacted proton pump inhibiting agent greater than about 100 ng/ml within about 10 minutes after administration of the pharmaceutical composition.

In another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 150 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 150 ng/ml from about 15 minutes to about 1 hour after administration of the composition. In yet another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 250 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 250 ng/ml from about 15 minutes to about 1 hour after administration of the composition. In another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 350 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 350 ng/ml from about 15 minutes to about 1 hour after administration of the composition. In another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 450 ng/ml within about 15 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 450 ng/ml from about 15 minutes to about 1 hour after administration of the composition.

In another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 150 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 150 ng/ml from about 30 minutes to about 1 hour after administration of the composition. In yet another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 250 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 250 ng/ml from about 30 minutes to about 1 hour after administration of the composition. In another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 350 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 350 ng/ml from about 30 minutes to about 1 hour after administration of the composition. In another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of the proton pump inhibiting agent greater than about 450 ng/ml within about 30 minutes and to maintain a serum concentration of the proton pump inhibiting agent of greater than about 450 ng/ml from about 30 minutes to about 1 hour after administration of the composition.

In still another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of a non-acid degraded or non-acid reacted proton pump inhibiting agent greater than about 500 ng/ml within about 1 hour after administration of the composition. In yet another embodiment of the present invention, the composition is administered to the subject in an amount to achieve a measurable serum concentration of a non-acid degraded or non-acid reacted proton pump inhibiting agent greater than about 300 ng/ml within about 45 minutes after administration of the composition.

In another embodiment of the present invention, the composition is administered to the subject in an amount sufficient to achieve a maximum serum concentration (Cmax) at a time (Tmax) that is within about 90, 70, 60, 50, 40, 30 or 20 minutes after administration of the composition according to the present invention.

In still another embodiment of the invention, the composition is administered to the subject in an amount sufficient to achieve a maximum serum concentration (Cmax) at a time (Tmax) that is between about 10 and about 90 minutes, between about 10 to about 60 minutes, between about 15 to about 60 minutes or between about 20 to about 60 minutes after administration of the composition according to the present invention. In some specific embodiments, the values of Cmax and Tmax are averages over a test population. In other specific embodiments, the values of Cmax and Tmax are the values for an individual.

In still another embodiment, the composition is administered in an amount sufficient to achieve a maximum serum concentration (Cmax) of from about 400 to about 2000 ng/mL, from about 400 to about 1500 ng/mL, from about 1000 to about 1500 ng/mL , from about 400 to about 1000 ng/mL or from about 400 to about 700 ng/mL. In some specific embodiments, the values of Cmax and Tmax are averages over a test population. In other specific embodiments, the values of Cmax and Tmax are the values for an individual.

In a further embodiment, the composition is administered in an amount sufficient to achieve a maximum serum concentration (Cmax) of greater than 400 ng/mL, greater than 600 ng/mL, greater than 1000 ng/mL. In some specific embodiments, the values of Cmax and Tmax are averages over a test population. In other specific embodiments, the values of Cmax and Tmax are the values for an individual.

In one embodiment of the present invention, the composition is administered to a subject in a gastrointestinal-disorder-effective amount, that is, the composition is administered in an amount that achieves a therapeutically-effective dose of a proton pump inhibiting agent in the blood serum of a subject for a period of time to elicit a desired therapeutic effect. Illustratively, in a fasting adult human (fasting for generally at least 10 hours) the composition is administered to achieve a therapeutically-effective dose of a proton pump inhibiting agent in the blood serum of a subject within about 45 minutes after administration of the composition. In another embodiment of the present invention, a therapeutically-effective dose of the proton pump inhibiting agent is achieved in the blood serum of a subject within about 30 minutes from the time of administration of the composition to the subject. In yet another embodiment, a therapeutically-effective dose of the proton pump inhibiting agent is achieved in the blood serum of a subject within about 20 minutes from the time of administration to the subject. In still another embodiment of the present invention, a therapeutically-effective dose of the proton pump inhibiting agent is achieved in the blood serum of a subject at about 15 minutes from the time of administration of the composition to the subject.

In further embodiments, the oral bioavailability of the proton pump inhibitor is at least about 25%. In other embodiments, the oral bioavailability of the proton pump inhibitor is at least about 30%. In still other embodiments, the oral bioavailability of the proton pump inhibitor is at least 35%, or at least 40%, or at least 45%, or at least 50%, or at least 55% bioavailable, or at least 60%.

In alternative embodiments, the pharmaceutical composition comprises at least about 5 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. In other embodiments, the pharmaceutical composition comprises between about 5 mEq to about 30 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. In still other embodiments, the pharmaceutical composition comprises between about 5 mEq to about 30 mEq, or about 5 mEq, or about 7 mEq, or about 10 mEq, or about 13 mEq, or about 15 mEq, or about 17 mEq, or about 20 mEq, or about 22 mEq, or about 25 mEq, or about 27 mEq, or about 30 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. “Bioequivalent” is intended to mean that the area under the serum concentration time curve (AUC) and the peak serum concentration (C_(max)) are each within 80% and 120%.

In alternative embodiments, the pharmaceutical composition comprises at least about 5 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. In other embodiments, the pharmaceutical composition comprises between about 5 mEq to about 11 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®. In still other embodiments, the pharmaceutical composition comprises between about 5 mEq to about 11 mEq, or about 5 mEq, or about 6 mEq, or about 7 mEq, or about 8 mEq, or about 9 mEq, or about 10 mEq, or about 11 mEq of antacid and is bioequivalent to a proton pump inhibitor product such as Priolosec®, Nexium®, Prevacid®, Protonic®, or Aciphex®.

In other embodiments, when administered to a subject, the pharmaceutical composition has an area under the serum concentration time curve (AUC) for the proton pump inhibitor that is equivalent to the area under the serum concentration time curve (AUC) for the proton pump inhibitor when the enteric form of the proton pump inhibitor is delivered without antacid. “Equivalent” is intended to mean that the area under the serum concentration time curve (AUC) for the proton pump inhibitor is within ±30% of the area under the serum concentration time curve (AUC) when the same dosage amount of the proton pump inhibitor is enterically coated and delivered to the subject with less than 1 mEq of antacid. The “enteric form of the proton pump inhibitor” is intended to mean that some or most of the proton pump inhibitor has been enterically coated to ensure that at least some of the drug is released in the proximal region of the small intestine (duodenum), rather than the acidic environment of the stomach.

In yet other embodiments, the pharmaceutical compositions provide a release profile of the proton pump inhibitor, using USP dissolution methods, whereby greater than about 50% of the proton pump inhibitor is released from the composition within about 2 hours; or greater than 50% of the proton pump inhibitor is released from the composition within about 1.5 hours; or greater than 50% of the proton pump inhibitor is released from the composition within about 1 hour after exposure to gastrointestinal fluid. In another embodiment, greater than about 60% of the proton pump inhibitor is released from the composition within about 2 hours; or greater than 60% of the proton pump inhibitor is released from the composition within about 1.5 hours; or greater than 60% of the proton pump inhibitor is released from the composition within about 1 hour after exposure to gastrointestinal fluid. In yet another embodiment, greater than about 70% of the proton pump inhibitor is released from the composition within about 2 hours; or greater than 70% of the proton pump inhibitor is released from the composition within about 1.5 hours; or greater than 70% of the proton pump inhibitor is released from the composition within about 1 hour after exposure to gastrointestinal fluid.

Compositions contemplated by the present invention provide a therapeutic effect as proton pump inhibiting agent medications over an interval of about 5 minutes to about 24 hours after administration, enabling, for example, once-a-day, twice-a-day, or three times a day administration if desired. Generally speaking, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vivo for a period of time effective to elicit a therapeutic effect. Determination of these parameters is well within the skill of the art.

Dosage Forms

The pharmaceutical compositions of the present invention contain desired amounts of proton pump inhibitor and antacid and can be in the form of: a tablet, (including a suspension tablet, a chewable tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC) a lozenge, a sachet, a troche, pellets, granules, or an aerosol. The pharmaceutical compositions of the present invention can be manufactured by conventional pharmacological techniques.

In some embodiments, the pharmaceutical compositions of the present invention contain desired amounts of proton pump inhibiting inhibitor and antacid and are in a solid dosage form. In other embodiments, the pharmaceutical compositions of the present invention contain desired amounts of proton pump inhibitor and antacid and are administered in the form of a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatineor plant-derived HPMC). The pharmaceutical compositions of the present invention can be manufactured by conventional pharmacological techniques.

Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, e.g., prilling, spray drying, pan coating, melt granulation, granulation, wurster coating, tangential coating, top spraying, extruding, coacervation and the like.

In one embodiment, the proton pump inhibitor is microencapsulated prior to being formulated into one of the above forms. In another embodiment, some of the proton pump inhibitor is microencapsulated prior to being formulated. In another embodiment, some or all of the antacid is microencapsulated prior to being formulated. In still another embodiment, some or most of the proton pump inhibitor is coatedprior to being further formulated by using standard coating procedures, such as thcise described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In yet other embodiments contemplated by the present invention, a film coating is provided around the pharmaceutical composition.

In other embodiments, the pharmaceutical compositions further comprise one or more additional materials such as a pharmaceutically compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, surfactant, preservative, lubricant, colorant, diluent, solubilizer, moistening agent, stabilizer, wetting agent, anti-adherent, parietal cell activator, anti-foaming agent, antioxidant, chelating agent, antifungal agent, antibacterial agent, or one or more combination thereof.

In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, e.g., diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

Exemplary Solid Oral Dosage Compositions

Solid oral dosage compositions, e.g., tablets, chewable tablets, effervescent tablets, caplets, and capsules, can be prepared, for example, by mixing the proton pump inhibitor, one or more antacid, and pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it is meant that the proton pump inhibitor and antacid are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The individual unit dosages may also comprise film coatings, which disintegrate upon oral ingestion or upon contact with diluent.

Compressed tablets are solid dosage forms prepared by compacting the bulk blend compositions described above. In various embodiments, compressed tablets of the present invention will comprise one or more functional excipients such as binding agents and/or disintegrants. In other embodiments, the compressed tablets will comprise a film surrounding the final compressed tablet. In other embodiments, the compressed tablets comprise one or more excipients and/or flavoring agents.

A chewable tablet may be prepared by compacting bulk blend compositions, described above. In one embodiment, the chewable tablet comprises a material useful for enhancing the shelf life of the pharmaceutical composition. In another embodiment, the microencapsulated material has taste-masking properties. In various other embodiments, the chewable tablet comprises one or more flavoring agents and one or more taste-masking materials. In yet other embodiments the chewable tablet comprised both a material useful for enhancing the shelf life of the pharmaceutical formulation and one or more flavoring agents.

In various embodiments, the proton pump inhibitor, antacid, and optionally one or more excipients, are dry blended and compressed into a mass, such as a tablet or caplet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the antacid and the proton pump inhibitor into the gastrointestinal fluid. When at least 50% of the pharmaceutical composition has disintegrated, the compressed mass has substantially disintegrated.

A capsule may be prepared by placing any of the bulk blend compositions described above, into a capsule. In some embodiments of the present invention, the therapeutic dose is split into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the proton pump inhibitor and antacid are delivered in a capsule form. For example, the capsule may comprise between about 10 mg to about 120 mg of a proton pump inhibitor and between about 5 mEq to about 30 mEq of antacid. In some embodiments, the antacid may be selected from sodium bicarbonate, magnesium hydroxide, calcium carbonate, magnesium oxide, and mixtures thereof. In alternative embodiments the capsule comprises 5 mEq to about 30 mEq of sodium bicarbonate.

Exemplary Powder Compositions

A powder for suspension may be prepared by combining at least one acid labile proton pump inhibitor and between about 5 mEq to about 11 mEq of antacid. In various embodiments, the powder may comprise one or more pharmaceutical excipients and flavors. A powder for suspension may be prepared, for example, by mixing the proton pump inhibitor, one or more antacids, and optional pharmaceutical excipients to form a bulk blend composition. This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units. The term “uniform” means the homogeneity of the bulk blend is substantially maintained during the packaging process.

In some embodiments, some or all of the proton pump inhibitor is micronized. Additional embodiments of the present invention also comprise a suspending agent and/or a wetting agent.

Effervescent powders are also prepared in accordance with the present invention. Effervescent salts have been used to disperse medicines in water for oral administration. Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid. When salts of the present invention are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing “effervescence.” Examples of effervescent salts include, e.g., the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

The method of preparation of the effervescent granules of the present invention employs three basic processes: wet granulation, dry granulation and fusion. The fusion method is used for the preparation of most commercial effervescent powders. It should be noted that, although these methods are intended for the preparation of granules, the formulations of effervescent salts of the present invention could also be prepared as tablets, according to known technology for tablet preparation.

Powder for Suspension

In some embodiments, compositions are provided comprising a pharmaceutical at least one proton pump inhibitor, about 5 mEq to about 11 mEq of an antacid, and at least one suspending agent for oral administration to a subject. The composition may be a powder for suspension, and upon admixture with water, a substantially uniform suspension is obtained. See U.S. patent application Ser. No. 10/893,092, filed Jul. 16, 2004, which claims priority to U.S. Provisional Application No. 60/488,324 filed Jul. 18, 2003, both of which are herein incorporated by reference in their entirety.

A suspension is “substantially uniform” when it is mostly homogenous, that is, when the suspension is composed of approximately the same concentration of proton pump inhibitor at any point throughout the suspension. A suspension is determined to be composed of approximately the same concentration of proton pump inhibitor throughout the suspension when there is less than about 20%, less than about 15%, less than about 13%, less than about 11%, less than about 10%, less than about 8%, less than about 5%, or less than about 3% variation in concentration among samples taken from various points in the suspension.

The concentration at various points throughout the suspension can be determined by any suitable means known in the art. For example, one suitable method of determining concentration at various points involves dividing the suspension into three substantially equal sections: top, middle and bottom. The layers are divided starting at the top of the suspension and ending at the bottom of the suspension. Any number of sections suitable for determining the uniformity of the suspension can be used, such as for example, two sections, three sections, four sections, five sections, or six or more sections.

In one embodiment, the composition comprises at least one proton pump inhibitor, between about 5 mEq to about 11 mEq of antacid, and a gum suspending agent, wherein the average particle size of the insoluble material is less than about 200 μm. In some embodiments, the average particle size of the insoluble material is less than about 100 μm. In other embodiments, the average particle size of the insoluble material is less than about 50 μm. The composition is a powder for suspension, and upon admixture with water, a first suspension is obtained that is substantially more uniform when compared to a second suspension comprising the proton pump inhibitor, the antacid, and suspending agent, wherein the suspending agent is not xanthan gum.

In another embodiment, the composition comprises omeprazole, sodium bicarbonate and xanthan gum. The composition is a powder for suspension, and upon admixture with water, a substantially uniform suspension is obtained. In yet another embodiment, the composition is a powder for suspension and comprises omeprazole, about 5 mEq to about 11 mEq sodium bicarbonate, xanthan gum, and at least one sweetener or flavoring agent.

Combination Therapy

The compositions and methods described herein may also be used in conjunction with other well known therapeutic reagents that are selected for their particular usefulness against the condition that is being treated. In general, the compositions described herein and, in embodiments where combinational therapy is employed, other agents do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

The particular choice of compounds used will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol. The compounds may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the patient, and the actual choice of compounds used. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.

It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, can be modified in accordance with a variety of factors. These factors include the type of gastric acid disorder from which the subject suffers, the proton pump inhibitor being administered, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the dosage regimens set forth herein. For example, proton pump inhibitors can be formulated to deliver rapid relief as well as sustained relief of a gastric acid related disorder.

The pharmaceutical agents which make up the combination therapy disclosed herein may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration. The two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents. The time period between the multiple administration steps may range from, a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent. Circadian variation of the target molecule concentration may also determine the optimal dose interval.

In some embodiments, the present methods, kits, and compositions can be used in combination with another pharmaceutical agent that is indicated for treating or preventing a gastrointestinal disorder, such as, for example, an anti-bacterial agent, an alginate, a prokinetic agent, or an H₂-antagonist which are commonly administered to minimize the pain and/or complications related to this disorder. These drugs have certain disadvantages associated with their use. Some of these drugs are not completely effective in the treatment of the aforementioned conditions and/or produce adverse side effects, such as mental confusion, constipation, diarrhea, and thrombocytopenia.

In other embodiments, the present methods, kits, and compositions can be used in combination with other pharmaceutical agents, including but not limited to: NSAIDs including but not limited to aminoarylcarboxylic acid derivatives such as enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, and tolfenamic acid; arylacetic acid derivatives such as aceclofenac, acemetacin, alclofenac, amfenac, amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac isoxepac, lonazolac, metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide, tolmetin, tropesin, and zomepirac; arylbutyric acid derivatives such as bumadizon, butibufen, fenbufen, xenbucin; arylcarboxylic acids such as clidanac, ketorolac, tinoridine; aryipropionic acid derivatives such as alminoprofen, benoxaprofin, bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, piketoprofin, pirprofen, pranoprofen, protizinic acid, suprofen, tiaprofenic acid, ximoprofen, and zaltoprofen;

pyrazoles such as difenamizole, and epirozole; pyrazolones such as apazone, benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, prostaglandins, ramifenazone, suxibuzone, and thiazolinobutazone; salicylic acid derivatives such as acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphtyl salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalate, sulfasalazine; thiazinecarboxamides such as ampiroxicam, droxicam, isoxicam, lomoxicam, piroxicam, and tenoxicam; cyclooxygenase-II inhibitors (“COX-II”) such as Celebrex (Celecoxib), Vioxx, Relafen, Lodine, and Voltaren and others, such as epsilon-acetamidocaproic acid, s-adenosylmethionine, 3-amino-4-hydroxybutytic acid, amixetrine, bendazac, benzydamine, bucololome, difenpiramide, ditazol, emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol, paranyline, perisoxal, proquazone, tenidap and zilenton; sleep aids including but not limited to a benzodiazepine hypnotic, non-benzodiazepine hypnotic, antihistamine hypnotic, antidepressant hypnotic, herbal extract, barbiturate, peptide hypnotic, triazolam, brotizolam, loprazolam, lormetazepam, flunitrazepam, flurazepam, nitrazepam, quazepam, estazolam, temazepam, lorazepam, oxazepam, diazepam, halazepam, prazepam, alprazolam, chlordiazepoxide, clorazepate, an imidazopyridine or pyrazolopyrimidine hypnotic, zolpidem or zolpidem tartarate, zopiclone, eszopiclone, zaleplon, indiplone, diphenhydramine, doxylamine, phenyltoloxamine, pyrilamine, doxepin, amtriptyline, trimipramine, trazodon, nefazodone, buproprion, bupramityiptyline, an herbal extract such as valerian extract or amentoflavone, a hormone such as melatonin, or gabapeptin; motility agents, including but not limited to 5-HT inhibitors such as cisapride, domperidone, and metoclopramide, and agents useful for treating irritable bowel syndrome.

For the sake of brevity, all patents and other references cited herein are incorporated by reference in their entirety.

EXAMPLES

The present invention is further illustrated by the following examples, which should not be construed as limiting in any way. The experimental procedures to generate the data shown are discussed in more detail below. For all formulations herein, multiple doses may be proportionally compounded as is known in the art. The coatings, layers and encapsulations are applied in conventional ways using equipment customary for these purposes.

The invention has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation.

Example 1 Modified Fuchs Model for Antacid Selection

Samples were prepared and analyzed using a method that is a variation of the Fuchs' procedure described in the literature. The procedure described simulates a gastric environment with continuous acid influx. A description of experimental set-up and sample analysis is provided below. Changes may be made to these instructions after initial sample evaluation to optimize sample analysis and collection of relevant information.

Set-Up:

-   -   1. A glass sample vessel (˜150 mL capacity) containing 50 mL of         a standardized solution of 0.1 N HCl was placed into a water         bath set at 37° C. (±2° C.).     -   2. A second glass vessel containing >70 mL of a standardized         solution of 1.0 N HCl was placed into the same water bath.     -   3. The stir paddle was then placed into the sample vessel and         set at an appropriate speed. The speed of the stir paddle was         recorded and used for all samples analyzed. The speed of the         paddle should be adequate to dissolve the sample and added acid         without causing interference with the pH measurement or         splashing of the solution.     -   4. Prior to the start of each sample analysis, the tubing was         primed and it was verified that the flow rate with 1.0 N HCl was         0.5 mL/min and the temperature was 37° C. (±2° C.). The pump and         tubing were then set-up to allow the transfer of 1.0 N HCl acid         into the sample vessel.     -   5. The pH meter was calibrated to accurately measure pH between         1 and 10 and it was verified that the electronic storage device         was ready to collect pH and/or temperature data at a pre-defined         rate.     -   6. When necessary, the sample was crushed into a fine powder         using a mortar and pestle and then transferred to a suitable         container and weighed.     -   7. The pH probe was placed into the glass sample vessel         containing 50 mL of 0.1 N HCl at 37° C. (±2° C.).     -   8. The timer and pH data collection was then started. The sample         was then transferred into the vessel and the exact time that the         sample was introduced into the acid was recorded. The sample         container was then re-weighed to determine the exact weight         added.     -   9. The sample was then stirred for approximately 6 minutes and         the flow of the 1.0 N HCl at a rate of 0.5 mL/min was started.         The exact start time of the acid flow was recorded.     -   10. For samples with not more than (≤) 30 mEq ANC the sample         continued to stir and the pH was monitored for 1 hour in 15         second intervals.     -   11. The duration of the test was recorded and the total volume         of 0.1 N HCl added was calculated based on the flow rate.

Various buffer combinations were screened using this modified Fuchs in-vitro dynamic stomach model, described above, and it was discovered that the correlation of the theoretical ANC of a given buffer to the actual neutralization capacity and the speed depended on several factors such as solubility, particle size, presence and level of binders and/or disintegrants. For example, it was determined that the smaller the particle size of the buffer the closer the theoretical value was to the actual ANC of a given buffer. This particle size effect was especially noticeable for the insoluble or sparingly soluble antacids such as calcium carbonate or magnesium hydroxide. Contrastingly, the larger the particles size of the antacids, the lower the actual ANC was (e.g., sub-100 US mesh size, sub-80 US mesh size, and sub-60 mesh size of Magnesium Hydroxide).

It was also determined that spray dried magnesium hydroxide with 5% starch such as MS-90® from SPI Pharma performed better than the USP grade manufactured by precipitation (USP grade Magnesium Hydroxide) in the on set speed of neutralization. In similar pattern, It spray dried calcium carbonate with 5% starch such as Destab® Calcium carbonate-95S from Particle Dynamics performed better than the USP grade calcium carbonate manufactured by precipitation in the on set speed of neutralization as well as the actual neutralization capacity measured by the area under curve (AUC) of the dynamic pH profile.

Example 2 Disintegrant Optimization Trials: Mixed Buffer System

Most proton pump inhibitors are sparingly soluble in water. These sparingly soluble drugs have a strong correlation of disintegration time to bioavailability, and it is important to optimize the disintegration time, which enhances in vivo dissolution of the drug. This trial used a sub-80 mesh US mesh size magnesium hydroxide based formulation as shown in Table 2.A.1 and tested levels between 3% and 11% levels of disintegrant (Croscarmellose Sodium, Ac-di-Sol) for the capsule dosage form performance. Disintegration test outlined by USP (United State Pharmacopia) was chosen as the test method to determine the optimal level of disintegrant. All capsule products containing between 5% to 11% Ac-Di-Sol performed similarly in terms of their physical characteristic, flow properties, and encapsulation characteristics. Disintegration testing of samples with mixed buffer systems indicated that capsule disintegration time is reduced when the level of disintegrant is increased from 3% to 5%. Increasing the level of disintegrant beyond 5% did not lower the disintegration time significantly.

Capsules were filled on a Pharm Op Zansi® LZ-64 dosator encapsulator using the compositions set forth in Table 2.A.1, below. The results of the disintegration study are shown in Table 2.A.2, below.

TABLE 2.A.1 Disintegrant Optimization Trials SAN-10D1 SAN-10D2 SAN-10D3 SAN-10D4 3% 5% 8% 11% Disintegrant Disintegrant Disintegrant Disintegrant Ingredients Mg/cap % Mg/cap % Mg/cap % Mg/cap % OMEPRAZOLE USP 40.8 4.1 40.8 4.1 40.8 3.9 40.8 3.8 Sodium Bicarbonate #2 USP 420 43.4 420 42.6 420 41.2 420 39.9 Magnesium Hydroxide 470 48.6 470 47.7 470 46.2 470 44.6 (sieved) sub 80 mesh Croscarmellose Sodium NF 30 3.1 49 5.0 81 8.0 116 11.0 Magnesium Stearate NF 7 0.7 7 0.7 7 0.7 7 0.7 Totals: 967 100.0 986 100.0 1018 100.0 1053 100.0

TABLE 2.A.2 Disintegrant Optimization Trials Disintegration Times Trial Number/Description First Last Comments/Observations SAN-10D1 (3% Ac-Di-Sol) 9′10″ 11′20″ Virtually all disintegrated at 9 mins. SAN-10D2 (5% Ac-Di-Sol) 7′30″ 12′ Virtually all disintegrated at 7 mins 30 secs. SAN-10D3 (8% Ac-Di-Sol) 8′ 11′ Virtually all disintegrated at 7 mins. SAN-10D4 (11% Ac-Di-Sol) 7′30″ 10′30″ Virtually all disintegrated at 7 mins.

Example 2B Disintegrant Optimization Trials—Sodium Bicarbonate Buffer

Sodium bicarbonate has effervescent characteristic when mixed with acid such as gastric fluid. This facilitates the disintegration time of a capsule product, and the disintegration requirement would be less than that of the mixed buffer system when sodium bicarbonate is used as a single buffer. This trial used a USP#2 grade sodium bicarbonate based formulation as shown in table 2.B.1. and tested levels between 1% and 5% levels of disintegrant (Croscarmerllose Sodium, Ac-di-Sol) for the capsule dosage form performance. Disintegration test outlined by USP (United State Pharmacopia) was chosen as the test method to determine the optimal level of disintegrant. All capsule products containing between 1% to 5% Ac-Di-Sol performed similarly in terms of their physical characteristic, flow properties, and encapsulation characteristics. However, disintegration testing of samples indicated that capsule disintegration time is reduced when the level of disintegrant is increased from 1% to 2%. Increasing the level of disintegrant beyond 3% did not lower the disintegration time significantly.

TABLE 2.B.1 Disintegrant Optimization Trials SAN-10BB1 SAN-10BB2 SAN-10BB3 SAN-10BB4 1% 2% 3% 5% Disintegrant Disintegrant Disintegrant Disintegrant Ingredients Mg/cap % Mg/cap % Mg/cap % Mg/cap % OMEPRAZOLE USP 40 3.5 40 3.4 40 3.4 40 3.3 Sodium Bicarbonate #2 USP 1100 94.9 1100 94.0 1100 93.1 1100 91.1 Croscarmellose Sodium NF 12 1.0 23 20. 35 3.0 60 5.0 Magnesium Stearate NF 7 0.6 7 0.6 7 0.6 7 0.6 Totals: 967 100.0 986 100.0 1018 100.0 1053 100.0

TABLE 2.B.2 Disintegrant Optimization Trials: Sodium Bicarbonate Buffer Disintegration Times Trial Number/Description First Last Comments/Observations SAN-10BB1 (1% Ac-Di-Sol) 6′40″ 8′20″ Virtually all disintegrated at 7 mins. SAN-10BB2 (2% Ac-Di-Sol) 4′30″ 6′ Virtually all disintegrated at 5 mins 30 secs. SAN-10BB3 (3% Ac-Di-Sol) 4′ 5′30″ Virtually all disintegrated at 5 mins. SAN-10BB4 (5% Ac-Di-Sol) 4′ 5′30″ Virtually all disintegrated at 5 mins.

Example 3 Binder Optimization Trials

A low level of binder 3-8% is commonly used in capsule product manufacturing to make a plug before encapsulation. The use of the binder such as Klucel®-EXP (hydroxypropyl cellulose) or microcrystalline cellulose (Avicel® PH-102, PH-200) was evaluated with the presence of 0-5% of disintegrant in the powder for the performance using the dynamic stomach model (modified Fuchs model). In general use of the binder had a negative impact on the actual ANC and the speed of neutralization in the pH profiling tests, unless used in combination with a disintegrant.

TABLE 3.A.1 Binder Optimization Trials SAN-10F1 SAN-10F2 SAN-10F3 SAN-10F4 SAN-10F5 Ingredients Mg/cap % Mg/cap % Mg/cap % Mg/cap % Mg/cap % Omeprazole USP 40.0 4.5 40.0 4.0 40.0 3.8 40.0 3.6 40.0 3.6 Sodium Bicarbonate #2 250 27.9 250 25.1 350 33.4 350 31.9 350 31.9 USP Magnesium Hydroxide 600.0 66.9 600.0 60.2 600.0 57.3 600.0 54.7 600.0 54.7 Klucel-EXP 0 0.0 100 10.0 50 4.8 100 9.1 50 4.6 Croscarmellose Sodium 0 0.0 0 0.0 0 0.0 0 0.0 50 4.6 NF Magnesium Stearate 7 0.8 7 0.7 7 0.7 7 0.6 7 0.6 NF Totals: 897.0 100.0 997.0 100.0 997.0 100.0 1,097.0 100.0 1,097.0 100.0

TABLE 3.A.2 Binder Optimization Trials TR2001 TR2002 TR2003 TR2004 TR2005 Ingredients Mg/cap % Mg/cap % Mg/cap % Mg/cap % Mg/cap % Omeprazole USP 40 4.5 40 4.0 40 4.0 40 3.6 40 3.6 Sodium 450 50.2 450 45.1 450 45.1 450 41.0 450 41.0 Bicarbonate #2 USP Magnesium 500 55.7 500 50.2 500 50.2 500 45.6 500 45.6 Hydroxide Klucel-EXP 20 2.2 20 2.0 50 5.0 50 4.6 0 0.0 Croscarmellose 20 2.2 50 5.0 50 5.0 20 1.8 20 1.8 Sodium NF Magnesium 7 0.8 7 0.7 7 0.7 7 0.6 7 0.6 Stearate NF Totals: 897 100.0 997 100.0 997 100.0 1,097.0 100.0 1,097.0 100.0

The pH test results (table 3.A.1. and table 3.A.2.) shows that hand-filled capsules with the binders at 5-10% level had a very slow neutralization speed while the capsule with binder and disintegrant had an adequate speed of neutralization. The capsules with no binder and no disintegrant showed a medium neutralization speed. Table 3BB showed the similar findings that the presence of binder slows down the neutralization speed while use of disintegrant mitigate the negative impact of binder in the formulation.

TABLE 3.B.1 Neutralization Speed of Capsules with Various Level of Binder and Disintegrant Binder Dis- Total Level integrant ANC Total Time Above pH (min) Sample (%) Level (%) (mEq) 3.5 5.0 6.0 6.5 SAN- 0 0 23.6 14.75 11.25 5.75 1.50 10F1 SAN- 10 0 23.6 0 0 0 0 10F2 SAN- 0 4.8 24.7 19.5 18.25 12.2 6.50 10F3 SAN- 9.1 4.8 24.7 15.45 11.30 9.50 7.45 10F4 SAN- 4.6 4.6 24.7 34.25 30.00 22.50 15.25 10F5

TABLE 3.B.2 Neutralization Speed of Capsules with Various Level of Binder and Disintegrant Binder Total Level Disintegrant ANC Total Time Above pH (min) Sample (%) Level (%) (mEq) 3.5 5.0 6.0 6.5 TR2001 2.2 2.2 22.5 8.5 7.00 0.25 0 TR2002 2.0 5.0 22.5 0.25 0 0 0 TR2003 5.0 5.0 22.5 7.25 6.00 0.25 0 TR2004 4.6 1.8 22.5 0 0 0 0 TR2005 0.0 1.8 22.5 0 0 0 0

Example 4 Capsule Formulations

The following formulations were prepared by the following process: The sodium bicarbonate and omeprazole were combined in a mixer and blended for 5 minutes. To that mixture, the magnesium hydroxide (if any) and croscarmellose sodium were added and mixed for 5 minutes. The blend was then passed through a #20 mesh s/s screen and then mixed for 10 minutes. Magnesium stearate was then added to the mixture and blended for 3 minutes. The material was then encapsulated into hard gelatin capsule shells using a Profill® manual capsule filler.

SAN-10A SAN-10B SAN-10BB SAN-10C Ingredients Mg/caps Mg/caps Mg/caps Mg/caps OMEPRAZOLE USP 40 40 40 20 Sodium Bicarbonate #2 USP 420 420 1100 800 Magnesium Hydroxide (sieved) 470 0 0 0 100 mesh Magnesium Hydroxide (sieved) 0 470 0 0 60 mesh Croscarmellose Sodium NF 30 30 20 20 Magnesium Stearate NF 10 10 10 8 Totals: 970 970 1170 848 SAN-10D SAN-10E SAN-10F SAN-10G SAN-10H Ingredients Mg/caps Mg/caps Mg/caps Mg/caps Mg/caps OMEPRAZOLE USP 40 40 40 40 40 Sodium Bicarbonate #2 USP 420 378 335 378 420 Magnesium Hydroxide (sieved) 470 0 0 0 0 80 mesh Magnesium Hydroxide (sieved) 0 0 375 0 375 60 mesh Magnesium Hydroxide 95-MS 0 447.4 0 447.4 0 Croscarmellose Sodium NF 30 27 24 56 82 Magnesium Stearate NF 7 6 5 6 5 Totals: 967 898.4 779.8 928 922

Example 5 Capsule Formulations with Sodium Bicarbonate and Less than 3% Disintegrant

The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI as well as sufficient buffering agent to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of buffer are expressed in weight as well as in molar equivalents (mEq). The capsules are prepared by blending the PPI with one or more buffering agents, and homogeneously blending with excipients. The appropriate weight of bulk blend composition is filled into a hard gelatine capsule (e.g., size 00) using an automatic encapsulator. The PPI can be in a micronized form.

PPI Buffering Agent Excipient 40 mg 11.3 mEq or 950 mg NaHCO₃ 50 mg Klucel omeprazole 30 mg Ac-di-Sol 10 mg magnesium stearate 2.8% disintegrant

PPI Buffering Agent Excipient 40 mg 10.5 mEq or 880 mg NaHCO₃ 30 mg Klucel omeprazole 20 mg Crospovidone 10 mg magnesium stearate 2.0% disintegrant

PPI Buffering Agent Excipient 60 mg 11.4 mEq or 960 mg NaHCO₃ 20 mg MCC omeprazole 25 mg Ac-Di-Sol per capsule 10 mg magnesium stearate 1.9% disintegrant

Example 6 Capsule Formulations with Mixed Buffer Systems and 3-11% Disintegrant

The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI as well as sufficient buffering agent to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of buffer are expressed in weight as well as in molar equivalents (mEq). The capsules are prepared by blending the PPI with one or more buffering agents, and homogeneously blending with excipients. The appropriate weight of bulk blend composition is filled into a hard gelatinecapsule (e.g., size 00) using an automatic encapsulator. The PPI can be in a micronized form.

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂ 20 mg MCC omeprazole 3 mEq or 250 mg NaHCO₃ 50 mg Ac-di-Sol 23.6 mEq or 950 mgs total 10 mg magnesium buffer stearate 5.2% disintegrant

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂ 100 mg MCC omeprazole 3 mEq or 250 mg NaHCO₃ 50 mg Ac-di-Sol 23.6 mEq or 950 mgs total 10 mg magnesium buffer stearate 4.8% disintegrant

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂ 30 mg MCC omeprazole 3 mEq or 250 mg NaHCO₃ 100 mg sodium starch 23.6 mEq or 950 mgs total glycolate (Primojel ®) buffer 10 mg magnesium stearate 9.7% disintegrant

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂ 50 mg Klucel omeprazole 3 mEq or 250 mg NaHCO₃ 50 mg Ac-di-Sol 23.6 mEq or 850 mgs total 10 mg magnesium buffer stearate 5.0% disintegrant

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂ 30 mg Klucel omeprazole 3 mEq or 250 mg NaHCO₃ 30 mg Ac-di-Sol 23.6 mEq or 850 mgs total 10 mg magnesium buffer stearate 3.1% disintegrant

PPI Buffering Agent Excipient 20 mg 20.6 mEq or 600 mg Mg(OH)₂ 100 mg Klucel omeprazole 3 mEq or 250 mg NaHCO₃ 30 mg Ac-di-Sol 23.6 mEq or 850 mgs total 10 mg magnesium buffer stearate 3.0% disintegrant

PPI Buffering Agent Excipient 20 mg 20.6 mEq or 600 mg Mg(OH)₂ 30 mg Klucel omeprazole 3.0 mEq or 250 mg NaHCO₃ 70 mg Crospovidone 23.6 mEq or 850 mgs total 10 mg magnesium buffer stearate 7.1% disintegrant

PPI Buffering Agent Excipient 20 mg 20.6 mEq or 600 mg Mg(OH)₂ 50 mg Ac-Di-Sol omeprazole 3.0 mEq or 250 mg NaHCO₃ 30 mg Klucel per capsule 23.6 mEq or 850 mgs total 10 mg magnesium buffer stearate 5.2% disintegrant

PPI Buffering Agent Excipient 20 mg 20.6 mEq or 600 mg Mg(OH)₂ 40 mg Ac-Di-Sol omeprazole 4.2 mEq or 350 mg NaHCO₃ 35 mg Klucel per capsule 24.7 mEq or 950 mg total 10 mg magnesium buffer stearate 4.1% disintegrant

PPI Buffering Agent Excipient 15 mg micro- 17.1 mEq or 500 mg Mg(OH)₂ 50 mg Ac-Di-Sol encapsulated 3.0 mEq or 250 mg NaHCO₃ 15 mg Klucel lansoprazole 20.7 1 mEq or 750 mg total 7 mg magnesium per capsule buffer stearate 6.0% disintegrant

PPI Buffering Agent Excipient 30 mg 17.1 mEq or 500 mg Mg(OH)₂ 40 mg Ac-Di-Sol lansoprazole 4.2 mEq or 350 mg NaHCO₃ 30 mg Klucel per capsule 21.3 mEq or 850 mg total 10 mg magnesium buffer stearate 4.2% disintegrant

PPI Buffering Agent Excipient 60 mg 17.1 mEq or 500 mg 30 mg Crospovidone ompeprazole per Mg(OH)₂ 15 mg Klucel capsule 3.0 mEq or 250 mg NaHCO₃ 7 mg magnesium 20.1 mEq or 750 mg total stearate buffer 3.5% disintegrant

PPI Buffering Agent Excipient 10 mg 17.1 mEq or 500 mg 30 mg sodium starch ompeprazole Mg(OH)₂ glycolate (Explotab ®) per capsule 3.0 mEq or 250 mg NaHCO₃ 15 mg Klucel 20.1 mEq or 750 mg total 7 mg magnesium stearate buffer 3.7% disintegrant

PPI Buffering Agent Excipient 20 mg 20.6 mEq or 600 mg 50 mg Ac-Di-Sol microencapsulated Mg(OH)₂ 50 mg Klucel omeprazole 3.0 mEq or 250 mg NaHCO₃ 10 mg magnesium per capsule 23.6 mEq or 850 mg total stearate buffer 5.1% disintegrant

PPI Buffering Agent Excipient 40 mg 17.1 mEq or 500 mg 40 mg Ac-Di-Sol omeprazole Mg(OH)₂ 45 mg Klucel per capsule 4.2 mEq or 350 mg NaHCO₃ 10 mg magnesium stearate 21.3 mEq or 850 mg total 4.1% disintegrant buffer

PPI Buffering Agent Excipient 15 mg 17.1 mEq or 500 mg 30 mg Crospovidone lansoprazole Mg(OH)₂ 15 mg Klucel per capsule 3.0 mEq or 250 mg NaHCO₃  7 mg magnesium stearate 20.1 mEq or 750 mg total 3.7% disintegrant buffer

PPI Buffering Agent Excipient 20 mg 17.1 mEq or 500 mg 50 mg Ac-Di-Sol omeprazole Mg(OH)₂ 30 mg Klucel per capsule 3.0 mEq or 250 mg NaHCO₃ 10 mg magnesium stearate 20.1 mEq or 750 mg total 5.8% disintegrant buffer

PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg 40 mg Ac-Di-Sol omeprazole Mg(OH)₂ 35 mg Klucel per capsule 4.2 mEq or 350 mg NaHCO₃ 10 mg magnesium stearate 24.8 mEq or 950 mg total 3.7% disintegrant buffer

PPI Buffering Agent Excipient 15 mg 17.1 mEq or 500 mg 60 mg Ac-Di-Sol microencapsulated Mg(OH)₂ 15 mg Klucel lansoprazole 3.0 mEq or 250 mg NaHCO₃ 7 mg magnesium per capsule 20.1 mEq or 750 mg total stearate buffer 7.1% disintegrant

PPI Buffering Agent Excipient 60 mg 17.1 mEq or 500 mg 30 mg Ac-Di-Sol ompeprazole Mg(OH)₂ 15 mg Klucel per capsule 3.0 mEq or 250 mg NaHCO₃  7 mg magnesium stearate 20.1 mEq or 750 mg total 3.5% disintegrant buffer

PPI Buffering Agent Excipient 20 mg 6.9 mEq or 200 mg 30 mg Ac-Di-Sol omeprazole Mg(OH)₂ 35 mg Klucel per capsule 3.9 mEq or 330 mg NaHCO₃ 6 mg magnesium Size 0 capsule 10.8 mEq or 530 mg total stearate buffer 4.8% disintegrant

PPI Buffering Agent Excipient 15 mg 6.9 mEq or 200 mg 35 mg Ac-Di-Sol microencapsulated Mg(OH)₂ 20 mg Klucel lansoprazole 2.6 mEq or 220 mg NaHCO₃ 6 mg magnesium per capsule 8.5 mEq or 420 mg total stearate Size 1 capsule buffer 7.1% disintegrant

PPI Buffering Agent Excipient 30 mg 3.4 mEq or 100 mg Mg(OH)₂ 20 mg Ac-Di-Sol lansoprazole 3.8 mEq or 315 mg NaHCO₃ 30 mg Klucel per capsule 7.2 mEq or 415 mg total 5 mg magnesium Size 1 capsule buffer stearate 4.0% disintegrant

PPI Buffering Agent Excipient 60 mg 5.1 mEq or 150 mg Mg(OH)₂ 20 mg Ac-Di-Sol ompeprazole 3.0 mEq or 250 mg NaHCO₃ 10 mg Klucel per capsule 8.1 mEq or 400 mg total  4 mg magnesium stearate Size 2 buffer 4.1% disintegrant V

PPI Buffering Agent Excipient 120 mg 8.6 mEq or 250 mg Mg(OH)₂ 30 mg Ac-Di-Sol ompeprazole 2.4 mEq or 200 mg NaHCO₃ 30 mg Klucel per capsule 11.0 mEq or 450 mg total  8 mg magnesium stearate Size 1 buffer 4.7% disintegrant capsule

PPI Buffering Agent Excipient 10 mg 3.4 mEq or 100 mg Mg(OH)₂ 18 mg Ac-Di-Sol ompeprazole 3.0 mEq or 250 mg NaHCO₃ 15 mg Klucel per capsule 6.4 mEq or 350 mg total  7 mg magnesium stearate Size 2 buffer 4.5% disintegrant capsule

Example 7A Capsule Formulations without Binder

The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI as well as sufficient buffering agent to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of buffer are expressed in weight as well as in molar equivalents (mEq). The capsules are prepared by blending the PPI with one or more buffering agents, and homogeneously blending with excipients. The appropriate weight of bulk blend composition is filled into a hard gelatine capsule (e.g., size 00) using an automatic encapsualtor. The PPI can be in a micronized form.

TABLE 7A PPI Buffering Agent Excipient 40 mg 20.6 mEq or 600 mg Mg(OH)₂ 50 mg Ac-di-Sol omeprazole 3.0 mEq or 250 mg NaHCO₃ 10 mg magnesium 23.6 mEq or 950 mgs total stearate buffer

TABLE 7B PPI Buffering Agent Excipient 40 mg micro- 15.4 mEq or 450 mg Mg(OH)₂ 30 mg Ac-Di-Sol encapsulated 2.4 mEq or 200 mg NaHCO₃ 7 mg magnesium ompeprazole 17.8 mEq or 650 mg total stearate per capsule buffer

TABLE 7C PPI Buffering Agent Excipient 40 mg 10.5 mEq or 880 mg NaHCO₃ 20 mg Ac-Di-Sol omeprazole 10.5 mEq or 880 mg total 9 mg magnesium stearate per capsule buffer Size 0 Elongated capsule

TABLE 7D PPI Buffering Agent Excipient 40 mg micro- 3.4 mEq or 100 mg Mg(OH)₂ 20 mg Ac-Di-Sol encapsulated 2.4 mEq or 200 mg NaHCO₃ 5 mg magnesium stearate ompeprazole 5.8 mEq or 300 mg total Size 2 capsule per capsule buffer

Example 7B 40 mg Omeprazole (SAN-7E)

The following specific formulations are provided by way of illustrating the present invention and are not intended to be limiting. The capsules were prepared by blending the indicated amount of micronized omeprazole USP (purchased from Union Quimico Farmaceutica, “UQUIFA”) about half the indicated amount of sodium bicarbonate USP #2. After blending the omeprazole and sodium bicarbonate, the remaining sodium bicarbonate USP #2 was added along with the indicated amount of croscarmellose sodium and magnesium stearate. Once the omeprazole was homogeneously blended with the excipients, the appropriate weight of composition was filled into hard gelatin capsules, size 00, using a dosing disc/tampling pin-type automatic encapsulator.

In particular, a 110 kg blend for manufacturing 40 mg/capsule omeprazole immediate release capsules according to the present invention was manufactured by the following procedure: First, about half of the sodium bicarbonate was blended with omeprazole in a 5 cubic foot V-blender. First, about one quarter of the total sodium bicarbonate (i.e. about 25% of 102.47 kg (the total amount of sodium bicarbonate USP #2) was passed through a 16/20 mesh screen and charged into the V-blender. Next, 3.80 kg of omeprazole USP were passed through a 16/20 mesh screen and charged into the V-blender. Then, about one quarter of the total sodium bicarbonate were passed through the 16/20 mesh screen and charged into the V-blender. Once the sodium bicarbonate (about half the total) and omeprazole were charged into the V-blender, they were mixed for 5 minutes to form a pre-blend.

Next, about half of the sodium bicarbonate and the crocarmellose was added to the pre-blend. Approximately one quarter of the of the total sodium bicarbonate was passed through a 16/20 mesh screen and charged into the V-blender. Then 2.79 kg of crocarmellose sodium NF, EP was passed through the 16/20 mesh screen and charged into the V-blender. Finally, the remaining one quarter of the sodium bicarbonate was passed through the screen and charged into the V-blender. The resulting mixture was 5 minutes, sampled for BU, mixed again for 5 minutes, sampled for BU, mixed again for 5 minutes, and sampled again for BU.

Last, magnesium stearate was added to the mixture. The magnesium stearate, 0.93 Kg, was passed through a 30 mesh screen and charged into the V-blender. The mixture was mixed for 3 minutes then discharged into a drum. The mixture was then sampled for BU and then encapsulated in size 00 hard gelatin capsules on a H&K tamping pin encapsulator.

The amounts of omeprazole and excipients used in this example are set forth in the following table:

TABLE 7E Acid Neutralizing Amount Content Required (meq per Ingredient % mg/capsule for 110 Kg: capsule) Omeprazole USP 3.5% 40.8* mg/ 3.80 Kg — caps Sodium Bicarbonate 93.2 1100 102.47 13.1 meq USP #2 Croscarmellose 2.5 30 2.79 — Sodium NF, EP Magnesium Stearate 0.8 10 0.93 — Total: 100.0 1180.8 110.00 13.1 *An overage of 2% of omeprazole was used to ensure at least 100% indicated omeprazole per capsule.

Example 7C 20 mg Omeprazole (SAN-7F)

In another particular example, a 1300 Kg blend of 20 mg omeprazole per capsule was manufactured by the following procedure:

First, about half of the sodium bicarbonate was blended with omeprazole in a 60 cubic foot V-blender. About one quarter of the total sodium bicarbonate (i.e. about 25% of 1232.33 kg (the total amount of sodium bicarbonate USP #2) was passed through a 16/20 mesh screen and charged into the V-blender. Next, 22.85 Kg of omeprazole USP were passed through the 16/20 mesh screen and charged into the V-blender. Then, about one quarter of the total sodium bicarbonate were passed through the 16/20 mesh screen and charged into the V-blender. Once the sodium bicarbonate (about half the total) and omeprazole were charged into the V-blender, they were mixed for 5 minutes to form a pre-blend.

Next, about half of the sodium bicarbonate and the croscarmellose was added to the pre-blend. Approximately one quarter of the of the total sodium bicarbonate was passed through a 16/20 mesh screen and charged into the V-blender. Then 33.61 Kg of Croscarmellose sodium NF, EP was passed through the 16/20 mesh screen and charged into the V-blender. Finally, the remaining one quarter of the sodium bicarbonate was passed through the screen and charged into the V-blender. The resulting mixture was mixed 5 minutes, sampled for batch uniformity (BU), mixed again for 5 minutes, sampled for BU, mixed again for 5 minutes, and sampled again for BU.

Last, magnesium stearate was added to the mixture. The magnesium stearate, 11.20 Kg, was passed through a 30 mesh screen and charged into the V-blender. The mixture was mixed for 3 minutes then discharged into a drum. The mixture was then sampled for BU and encapsulated in size 00 hard gelatin capsules on a H&K tamping pin encapsulator.

The amounts of omeprazole and excipients used in this example are set forth in the following table:

TABLE 7F Acid Neutralizing Amount Content Required (meq per Ingredient % mg/capsule for 110 Kg: capsule) Omeprazole USP 1.8% 20.4* mg/ 22.85 Kg — capsule Sodium Bicarbonate 94.8 1100.0 1232.33 13.1 meq USP #2 Croscarmellose 2.6 30.0 33.61 — Sodium NF, EP Magnesium Stearate 0.9 10.0 11.20 — Total: 100.1 1160.4 1300.00 13.1 *An overage of 2% omeprazole was used to ensure that each capsule contained at least 100% of the indicated dose of 20 mg/capsule.

Example 8 Capsule Formulations

The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI as well as sufficient antacid to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of antacid are expressed in weight as well as in molar equivalents (mEq). The capsules are prepared by blending the PPI with antacids, and homogeneously blending with excipients as shown in Tables 8.A. to 8.H. below. The appropriate weight of bulk blend composition is filled into a hard gelatine capsule (e.g., size 00) using an automatic encapsualtor (H & K 1500 or MG2 G60). The PPI can be in a micronized form.

TABLE 8.A Omeprazole (20 mg) Capsule PPI Antacid Excipient 20 mg 6.9 mEq or 200 mg Mg(OH)₂ 30 mg Ac-Di-Sol omeprazole 3.9 mEq or 330 mg NaHCO₃ 35 mg Klucel per capsule 10.8 mEq or 530 mg total 6 mg magnesium stearate antacid Size 0 capsule

TABLE 8.B Omeprazole (40 mg) Capsule PPI Antacid Excipient 40 mg 10.5 mEq or 880 mg NaHCO₃ 40 mg Ac-Di-Sol omeprazole 10.5 mEq or 880 mg total 9 mg magnesium stearate per capsule antacid Size 0 Elongated capsule

TABLE 8.C Lansoprazole (15 mg) Capsule PPI Antacid Excipient 15 mg micro- 6.9 mEq or 200 mg Mg(OH)₂ 35 mg Ac-Di-Sol encapsulated 2.6 mEq or 220 mg NaHCO₃ 20 mg Klucel lansoprazole 9.5 mEq or 420 mg total 6 mg magnesium stearate per capsule antacid Size 1 capsule

TABLE 8.D Lansoprazole (30 mg) Capsule PPI Antacid Excipient 30 mg 3.4 mEq or 100 mg Mg(OH)₂ 20 mg Ac-Di-Sol lansoprazole 3.8 mEq or 315 mg NaHCO₃ 30 mg Klucel per capsule 7.2 mEq or 415 mg total 5 mg magnesium stearate antacid Size 1 capsule

TABLE 8.E Omeprazole (60 mg) Capsule PPI Antacid Excipient 60 mg 5.1 mEq or 150 mg Mg(OH)₂ 20 mg Ac-Di-Sol omeprazole 3.0 mEq or 250 mg NaHCO₃ 10 mg Klucel per capsule 8.1 mEq or 400 mg total 4 mg magnesium stearate antacid Size 2 capsule

TABLE 8.F Omeprazole (60 mg) Capsule PPI Antacid Excipient 120 mg 8.6 mEq or 250 mg Mg(OH)₂ 30 mg Ac-Di-Sol omeprazole 2.4 mEq or 200 mg NaHCO₃ 30 mg Klucel per capsule 11.0 mEq or 450 mg total 8 mg magnesium stearate antacid Size 1 capsule

TABLE 8.G Omeprazole (10 mg) Capsule PPI Antacid Excipient 10 mg micro- 3.4 mEq or 100 mg Mg(OH)₂ 18 mg Ac-Di-Sol encapsulated 3.0 mEq or 250 mg NaHCO₃ 15 mg Microcrystalline omeprazole 6.4 mEq or 350 mg total Cellulose (MCC, PH per capsule antacid 102) 7 mg magnesium stearate Size 2 capsule

TABLE 8.H Omeprazole (40 mg) Capsule PPI Antacid Excipient 40 mg micro- 3.4 mEq or 100 mg Mg(OH)₂ 20 mg Ac-Di-Sol encapsulated 2.4 mEq or 200 mg NaHCO₃ 5 mg magnesium stearate omeprazole 5.8 mEq or 300 mg total Size 2 capsule per capsule antacid

Example 9 Tablet Formulations

The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI and sufficient antacid to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of antacid are expressed in weight as well as in molar equivalents (mEq). The tablets are prepared by blending the PPI and antacids, and homogeneously blending with excipients as shown in Tables 9.A. to 9.H. below. The appropriate weight of bulk blended composition is compressed using oval shaped toolings in a rotary press (Manesty Express) to achieve a hardness of 15-20 kPa. The PPI can be in a micronized form.

TABLE 9.A Omeprazole (20 mg) Tablet PPI Antacid Excipient 20 mg 5.1 mEq or 150 mg Mg(OH)₂ 30 mg Ac-Di-Sol omeprazole 4.8 mEq or 400 mg NaHCO₃ 65 mg Klucel per tablet 9.9 mEq or 550 mg total 10 mg magnesium stearate antacid

TABLE 9.B Omeprazole (40 mg) Tablet PPI Antacid Excipient 40 mg micro- 5.1 mEq or 150 mg Mg(OH)₂ 20 mg Ac-Di-Sol encapsulated 3.0 mEq or 250 mg NaHCO₃ 40 mg Microcrystalline omeprazole 8.1 mEq or 350 mg total cellulose (MCC, PH 102) per tablet antacid 7 mg magnesium stearate

TABLE 9.C Lansoprazole (15 mg) Tablet PPI Antacid Excipient 15 mg micro- 8.6 mEq or 250 mg Mg(OH)₂ 30 mg Ac-Di-Sol encapsulated 2.4 mEq or 200 mg NaHCO₃ 55 mg Plasdone lansoprazole 11.0 mEq or 450 mg total 8 mg magnesium stearate per tablet antacid

TABLE 9.D Lansoprazole (30 mg) Tablet PPI Antacid Excipient 30 mg 6.2 mEq or 180 mg Mg(OH)₂ 25 mg Ac-Di-Sol lansoprazole 4.2 mEq or 350 mg NaHCO₃ 55 mg Klucel per tablet 10.4 mEq or 430 mg total 8 mg magnesium stearate antacid

TABLE 9.E Omeprazole (60 mg) Tablet PPI Antacid Excipient 60 mg 7.5 mEq or 220 mg Mg(OH)₂ 20 mg Ac-Di-Sol omeprazole 3.0 mEq or 250 mg NaHCO₃ 60 mg Klucel per tablet 10.5 mEq or 470 mg total 10 mg magnesium stearate antacid

TABLE 9.F Omeprazole (20 mg) Tablet PPI Antacid Excipient 20 mg 7.5 mEq or 220 mg Mg(OH)₂ 20 mg Ac-Di-Sol omeprazole 2.4 mEq or 200 mg NaHCO₃ 60 mg Klucel per tablet 9.9 mEq or 420 mg total 8 mg magnesium stearate antacid

TABLE 9.G Omeprazole (10 mg) Tablet PPI Antacid Excipient 10 mg micro- 3.4 mEq or 100 mg Mg(OH)₂ 15 mg Ac-Di-Sol encapsulated 3.0 mEq or 250 mg NaHCO₃ 40 mg Klucel omeprazole 6.4 mEq or 350 mg total 6 mg magnesium stearate per tablet antacid

TABLE 9.H Omeprazole (40 mg) Tablet PPI Antacid Excipient 40 mg micro- 5.1 mEq or 150 mg Mg(OH)₂ 20 mg Ac-Di-Sol encapsulated 3.8 mEq or 315 mg NaHCO₃ 50 mg Microcrystalline omeprazole 8.9 mEq or 465 mg total Cellulose (MCC, PH per tablet antacid 102) 10 mg magnesium stearate

Example 10 Chewable Tablet Formulations

The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI and sufficient antacid to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of antacid are expressed in weight as well as in molar equivalents (mEq). The tablets are prepared by blending the PPI and antacids, and homogeneously blending with excipients as shown in Tables 10.A to 10.H. below. The appropriate weight of bulk blended composition is compressed using 17 mm FFBE toolings in a rotary press (Manesty Express) to achieve a hardness of 10-14 kPa. The PPI can be in a micronized form.

TABLE 10.A Omeprazole (20 mg) Chewable Tablet PPI Antacid Excipient 20 mg micro- 5.1 mEq or 150 mg Mg(OH)₂ 100 mg Xylitab encapsulated 3.8 mEq or 315 mg NaHCO₃ 30 mg Ac-Di-Sol omeprazole 8.9 mEq or 465 mg total 80 mg Klucel per tablet antacid 20 mg Sucralose 10 mg cherry flavor 10 mg magnesium stearate 1 mg Red #40 Lake

TABLE 10.B Omeprazole (40 mg) Chewable Tablet PPI Antacid Excipient 40 mg micro- 7.5 mEq or 220 mg Mg(OH)₂ 100 mg Dipac sugar encapsulated 2.4 mEq or 200 mg NaHCO₃ 20 mg Ac-Di-Sol omeprazole 9.9 mEq or 420 mg total 80 mg Klucel per tablet antacid 17 mg grape flavor 11 mg magnesium stearate 1 mg Red #40 Lake 1 mg Blue #2 Lake

TABLE 10.C Lansoprazole (15 mg) Chewable Tablet PPI Antacid Excipient 15 mg 5.1 mEq or 150 mg Mg(OH)₂ 80 mg Xylitab lansoprazole 2.4 mEq or 200 mg NaHCO₃ 25 mg Ac-Di-Sol per tablet 7.5 mEq or 350 mg total 70 mg Microcrystalline antacid Cellulose 50 mg Asulfame-K 15 mg grape flavor 10 mg magnesium stearate 1 mg red #40 lake 1 mg blue #2 lake

TABLE 10.D Lansoprazole (30 mg) Chewable Tablet PPI Antacid Excipient 30 mg micro- 5.1 mEq or 150 mg Mg(OH)₂ 70 mg Destab Sugar encapsulated 3.8 mEq or 315 mg NaHCO₃ 30 mg Ac-Di-Sol lansoprazole 8.9 mEq or 465 mg total 100 mg Klucel per tablet antacid 20 mg Asulfame-K 15 mg cherry flavor 9 mg magnesium stearate 1 mg Red #40 Lake

TABLE 10.E Omeprazole (60 mg) Chewable Tablet PPI Antacid Excipient 60 mg micro- 4.4 mEq or 220 mg Ca(OH)₂ 80 mg Xylitab encapsulated 3.6 mEq or 300 mg NaHCO₃ 30 mg Ac-Di-Sol omeprazole 8.0 mEq or 520 mg total 100 mg Klucel per tablet antacid 35 mg Sucralose 10 mg cherry flavor 9 mg magnesium stearate 2 mg Red #40 Lake

TABLE 10.F Omeprazole (60 mg) Chewable Tablet PPI Antacid Excipient 60 mg 3.0 mEq or 150 mg Ca(OH)₂ 70 mg Xylitab omeprazole 3.0 mEq or 250 mg NaHCO₃ 25 mg Ac-Di-Sol per tablet 6.0 mEq or 400 mg total 90 mg Microcrystalline antacid Cellulose (PH 102) 8 mg mint flavor 10 mg magnesium stearate

TABLE 10.G Omeprazole (10 mg) Chewable Tablet PPI Antacid Excipient 10 mg 8.0 mEq or 400 mg Ca(OH)₂ 110 mg Ditab Sugar omeprazole 3.6 mEq or 300 mg NaHCO₃ 30 mg Ac-Di-Sol per tablet 11.6 mEq or 700 mg total 20 mg Sucralose antacid 100 mg Klucel 15 mg mint flavor 15 mg magnesium stearate

TABLE 10.H Omeprazole (40 mg) Chewable Tablet PPI Antacid Excipient 40 mg micro- 7.5 mEq or 350 mg Ca(OH)₂ 70 mg Xylitab encapsulated 3.0 mEq or 250 mg NaHCO₃ 30 mg Ac-Di-Sol omeprazole 10.5 mEq or 600 mg total 10 mg Sucralose per tablet antacid 80 mg Klucel 10 mg mint flavor 8 mg magnesium stearate

Example 11 Bite-Disintegration Chewable Tablet Formulations

The following specific formulations are provided by, way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI and sufficient antacid to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of antacid are expressed in weight as well as in molar equivalents (mEq). The tablets are prepared by blending the PPI with antacids, and homogeneously blending with excipients as shown in Tables 11.A to 11.H. below. The appropriate weight of bulk blended composition is compressed using 10 mm FFBE toolings in a rotary press (Manesty Express) to achieve a hardness of 5-9 kPa. The PPI can be in a micronized form.

TABLE 11.A Omeprazole (20 mg) Bite-Disintegration Chewable Tablet PPI Antacid Excipient 20 mg 7.5 mEq or 350 mg Ca(OH)₂ 20 mg sucralose per tablet 3.0 mEq or 250 mg NaHCO₃ 40 mg Ac-Di-Sol 10.5 mEq or 600 mg total 30 mg pregelatinized starch antacid 30 mg Klucel 15 mg cherry flavor 8 mg magnesium stearate 1 mg Red #40 Lake

TABLE 11.B Omeprazole (40 mg) Bite-Disintegration Chewable Tablet PPI Antacid Excipient 40 mg  8.0 mEq or 400 mg Ca(OH)₂ 20 mg sucralose micro-  3.6 mEq or 300 mg NaHCO₃ 40 mg Ac-Di-Sol encapsulated 35 mg pregelatinized starch omeprazole 11.6 mEq or 700 mg total 25 mg Klucel per tablet 15 mg cherry flavor  8 mg magnesium stearate  1 mg Red #40 Lake

TABLE 11.C Lansoprazole (15 mg) Bite-Disintegration Chewable Tablet PPI Antacid Excipient 15 mg  7.9 mEq or 230 mg Mg(OH)₂ 20 mg sucralose lanso-  3.6 mEq or 300 mg NaHCO₃ 35 mg Ac-Di-Sol prazole 35 mg pregelatinized starch per tablet 11.5 mEq or 530 mg total 25 mg Klucel 17 mg grape flavor  8 mg magnesium stearate  1 mg Red #40 Lake  1 mg Blue #2 lake

TABLE 11.D Lansoprazole (30 mg) Bite-Disintegration Chewable Tablet PPI Antacid Excipient 30 mg 5.1 mEq or 150 mg Mg(OH)₂ 27 mg sucralose micro- 3.8 mEq or 315 mg NaHCO₃ 40 mg Ac-Di-Sol encapsulated 35 mg pregelatinized starch lanso- 8.9 mEq or 465 mg total 30 mg Microcrystalline prazole antacid Cellulose (PH101) per tablet 20 mg cherry flavor 10 mg magnesium stearate  2 mg Red #40 Lake

TABLE 11.E Omeprazole (60 mg) Bite-Disintegration Chewable Tablet PPI Antacid Excipient 60 mg 7.9 mEq or 230 mg Mg(OH)₂ 34 mg sucralose micro- 3.0 mEq or 250 mg NaHCO₃ 30 mg Ac-Di-Sol encapsulated 35 mg pregelatinized starch omeprazole 10.9 mEq or 480 mg total 30 mg Klucel per tablet antacid 25 mg cherry flavor 10 mg magnesium stearate  2 mg Red #40 Lake

TABLE 11.F Omeprazole (60 mg) Bite-Disintegration Chewable Tablet PPI Antacid Excipient 60 mg 7.0 mEq or 350 mg Ca(OH)₂ 30 mg sucralose omeprazole 3.0 mEq or 250 mg NaHCO₃ 40 mg Ac-Di-Sol per tablet 30 mg pregelatinized starch 10.0 mEq or 600 mg total 30 mg Klucel antacid 40 mg Xylitab  7 mg mint flavor 10 mg magnesium stearate

TABLE 11.G Omeprazole (10 mg) Bite-Disintegration Chewable Tablet PPI Antacid Excipient 10 mg 5.0 mEq or 250 mg Ca(OH)₂ 20 mg sucralose omeprazole 2.9 mEq or 240 mg NaHCO₃ 40 mg Ac-Di-Sol per tablet 30 mg pregelatinized starch 7.9 mEq or 490 mg total 30 mg Klucel antacid 15 mg cherry flavor  8 mg magnesium stearate  1 mg Red #40 Lake

TABLE 11.H Omeprazole (40 mg) Bite-Disintegration Chewable Tablet PPI Antacid Excipient 40 mg 8.0 mEq or 400 mg Ca(OH)₂ 30 mg sucralose micro- 2.9 mEq or 240 mg NaHCO₃ 40 mg Ac-Di-Sol encapsulated 30 mg pregelatinized starch omeprazole 10.9 mEq or 1590 mg total 30 mg Klucel per tablet antacid 40 mg Xylitab  7 mg mint flavor 10 mg magnesium stearate

Example 12 Powder for Suspension Formulations

The following specific formulations are provided by way of reference only and are not intended to limit the scope of the invention. Each formulation contains therapeutically effective doses of PPI and sufficient antacid to prevent acid degradation of at least some of the PPI by raising the pH of gastric fluid. The PPI can be in a micronized form.

TABLE 12.A Microencapsulated Omeprazole (20/40/60/120 mg) Powder for Suspension 1 2 3 4 5 6 7 8 9 10 Microencapsulated 20 20 20 40 40 40 60 60 120 120 Omeprazole Sodium Bicarbonate 200 220 300 140 160 200 300 280 150 200 Magnesium Hydroxide 250 170 150 250 170 150 170 150 100 150 Calcium Carbonate 0 0 0 0 100 150 0 100 0 150 Xylitol 300 (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Sucrose-powder 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 (sweetener) Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 80 Xanthan Gum 10 55 31 80 39 48 72 25 64 68 Peach Flavor 33 15 75 32 60 50 77 38 35 62 Peppermint 13 10 29 28 36 42 56 17 16 50 Total Weight 2586 2590 2755 2645 2705 2750 2815 2800 2610 2880 Total ANC 11.0 8.4 8.7 10.2 9.7 10.5 9.4 10.5 5.2 10.5

TABLE 12.B Omeprazole (20 mg) Powder for Suspension 1 2 3 4 5 6 7 8 9 10 Omeprazole 20 20 20 20 20 20 20 20 20 20 Sodium Bicarbonate 200 220 300 140 160 200 300 280 150 200 Magnesium Hydroxide 250 170 150 250 170 150 170 150 100 150 Calcium Carbonate 0 0 0 0 100 150 0 100 0 150 Xylitol 300 (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Sucrose-powder (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 80 Xanthan Gum 10 55 31 80 39 48 72 25 64 68 Peach Flavor 33 15 75 32 60 50 77 38 35 62 Peppermint 13 10 29 28 36 42 56 17 16 50 Total Weight 2586 2590 2755 2625 2685 2730 2775 2760 2510 2780 Total ANC 11.0 8.4 8.7 10.2 9.7 10.5 9.4 10.5 5.2 10.5

TABLE 12.C Omeprazole (40 mg) Powder for Suspension 1 2 3 4 5 6 7 8 9 10 Omeprazole 40 40 40 40 40 40 40 40 40 40 Sodium Bicarbonate 200 220 300 140 160 200 300 280 150 200 Magnesium Hydroxide 250 170 150 250 170 150 170 150 100 150 Calcium Carbonate 0 0 0 0 100 150 0 100 0 150 Xylitol 300 (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Sucrose-powder (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 80 Xanthan Gum 75 10 55 31 80 39 48 72 25 64 68 Peach Flavor 33 15 75 32 60 50 77 38 35 62 Peppermint 13 10 29 28 36 42 56 17 16 50 Total Weight 2606 2610 2775 2645 2705 2750 2795 2780 2530 2800 Total ANC 11.0 8.4 8.7 10.2 9.7 10.5 9.4 10.5 5.2 10.5

TABLE 12.D Omeprazole (60 mg) Powder for Suspension 1 2 3 4 5 6 7 8 9 10 Omeprazole 60 60 60 60 60 60 60 60 60 60 Sodium Bicarbonate 200 220 300 140 160 200 300 280 150 200 Magnesium Hydroxide 250 170 150 250 170 150 170 150 100 150 Calcium Carbonate 0 0 0 0 100 150 0 100 0 150 Xylitol 300 (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Sucrose-powder (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 80 Xanthan Gum 75 10 55 31 80 39 48 72 25 64 68 Peach Flavor 33 15 75 32 60 50 77 38 35 62 Peppermint 13 10 29 28 36 42 56 17 16 50 Total Weight 2626 2630 2795 2665 2725 2770 2815 2800 2550 2820 Total ANC 11.0 8.4 8.7 10.2 9.7 10.5 9.4 10.5 5.2 10.5

Example 13 Naked or Microencapsulated Omeprazole 40 mg Chewable Tablets, Capsules, and Caplets are Pharmacokinetically Bioequivalent to Prilosec® Delayed-Release Capsules 40 mg with Respect to Area Under the Curve (AUC)

This trial was conducted as an open-label, single-dose, crossover trial, with each subject receiving up to twelve different oral omeprazole formulations, one in each of the twelve treatment periods. Each dose was followed by a minimum 7-day washout. Omeprazole was administered at a dose of 40 mg. The amount of antacid used in the formulations varied as set forth in Table 13A. All formulations were administered with about 120 ml (4 oz) of water after an overnight fast and 1 hour prior to a standardized, high-fat breakfast. Within a given treatment period, the same treatment was administered to all subjects.

The omeprazole was delivered as either Prilosec® or as an immediate-release formulation according to the invention (i.e. without an enteric coating). Omeprazole was formulated as uncoated or microencapsulated granules a powder in a capsule, a caplet or in a compressed chewable tablet.

Selection of the exact formulation for each treatment period is set forth in Table 13A, below.

TABLE 13A The pharmacokinetic release trial periods 1-12 with the tested omeprazole dosage forms. (All dosage forms contained 40 mg omeprazole as follows: Prilosec ® 40 mg, or a capsule, tablet, or caplet form, 40 mg). Period Study Material 1 Prilosec ® (40 mg omeprazole) (Prilosec ®) 2 SAN - 10A Capsule, 21.1 mEq (420 mg SB & 470 mg (SAN - 10A) MH) Utilizes <100 mesh MH 3 Period 3 Tablet, 30.7 mEq (850 mg SB & 600 mg MH) (SAN - 15A) “Naked” OME & MS95 MH 4 SAN - 10B Capsule, 21.1 mEq (420 mg SB & 470 mg (SAN - 10B) MH) Utilizes <60 mesh MH 5 Period 5 Tablet, 30.7 mEq (850 mg SB & 600 mg MH) (SAN - 15B) with Klucel eAPI & MS95 MH 6 SAN - 10J Capsule, 19.1 mEq (378 mg SB & 425 mg MH) (SAN - 10J) Utilizes MS95 MH 7 Period 7 Tablet, 30.7 mEq (850 mg SB & 600 mg MH) (SAN - 15C) with Methocel eAPI & MS95 MH 8 SAN - 10H Capsule, 17.9 mEq (420 mg SB & 375 mg (SAN - 10H) MH) Utilizes <60 mesh MH 9 SAN - 10BB Capsule, 13.1 mEq (1100 mg SB) (SAN - 10BB) 10 Period 10 Caplet, 18.8 mEq (280 mg SB & 450 mg MH) (SAN - 15D) eAPI, MS95 MH & 4.9% disintegrant 11 SAN - 10C Capsule, 10.5 mEq (880 mg SB) (SAN - 10C) 12 Period 12 Caplet, 18.8 mEq (280 mg SB & 450 mg MH) (SAN - 15E) eAPI, MS95 MH & 7.9% disintegrant

Volunteers were screened for up to 14 days before baseline measurements of blood plasma levels of omeprazole. In each period, a standardized high-fat breakfast was given in the clinic 1 hour after dosing of omeprazole. Blood samples for determination of plasma omeprazole concentrations were collected for 12 hours post treatment.

Duration of Treatment

Including screening, subjects participated in this trial for up to 170 days.

Design Rationale

This trial was designed to assess the pharmacokinetics of immediate-release omeprazole chewable tablets, oral capsule and caplets versus the Prilosec® 40 mg delayed-release formulation. The duration of the trial for each subject was approximately 24 weeks, including up to 14 days for screening and a minimum 7 day wash-out period between omeprazole doses.

Data from 12 healthy male subjects were expected to provide adequate power to assess pharmacokinetics and safety using descriptive statistics. The descriptive statistics were assessed using the pharmacokinetic parameters: Tmax, Cmax, AUC(0-t), AUC(0-inf), T½ and kel. Safety evaluations were based on the occurrence (vel non) of adverse events, blood chemistry and hematology, use of concomitant medications and change from baseline in physical examination findings and vital signs.

As the study employed a single dose of omeprazole for each period of dosing, the analysis focused on Day 1 of dosing.

The time of drug administration (after an overnight fast and 1 hour prior to a meal) meets the regulatory guidance for bioequivalence (fasting) and anticipates actual use.

Treatments Administered:

The treatments administered to subjects in this trial are listed in Table 13A, above. In general, the treatment protocol entailed a 14 day assessment period, followed by a first period (Period 1) in which Prilosec® 40 mg delayed release capsule was administered to the subjects, after an overnight fast, and 1 hour prior to a standardized high-fat breakfast. Plasma sampling was conducted for 6 hour post-dose. Period 1 was followed by a 7-14 day washout period, during which the plasma levels of omeprazole were expected to decrease to a steady baseline. The second through twelfth periods (Periods 2-12) were conducted in a similar manner to Period 1, in each period substituting a dosage form according to the invention for the delayed-release formulation used in Period 1. The specific dosage forms used in the study are set forth in Table 13A, above. Each of the 12 healthy male volunteers received the same course of treatment without randomization.

Pharmacokinetic Sampling, Analytical Methods, and Parameters

Blood samples (3 mL) were obtained by venipuncture within 30 minutes before each dose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 300, 360 minutes (6 hours) after delivery of each dose during each trial period. Zero time was the time that the subject swallowed a capsule, caplet or chewable tablet of trial drug.

Plasma omeprazole concentrations were measured using a previously validated liquid chromatography mass spectrometry (LC-MSIMS) assay (MDS Pharma Services, Lincoln, Nebr.). The linear assay range was 5.0 to 750 ng/mL.

The following pharmacokinetic parameters were measured for each subject:

-   -   Plasma omeprazole concentration at each sampling time     -   Peak omeprazole plasma concentration (Cmax) and the time at         which Cmax is observed (Tmax) obtained directly from the data         without interpolation     -   Terminal elimination rate constant (Kel) determined from a         log-linear regression analysis of the terminal plasma omeprazole         concentrations     -   Half-life of drug elimination (T %) calculated as 0.693/Kel     -   Area under the plasma drug time-concentration curve calculated         from 0 time to last time point evaluated [AUC(0-t)] calculated         using the trapezoidal rule with the plasma concentration at time         t being the last measurable concentration     -   Area under the plasma drug time-concentration curve calculated         from 0 time and extrapolated to infinity [AUC(0-inf)] calculated         as AUC(0-t)+Ct/Kel, where Ct is the last measurable plasma         concentration (at time t) and Kel is the terminal elimination         rate constant defined above

Primary Endpoint

The primary pharmacokinetic endpoint was the bioavailability of omeprazole [AUC(0-inf)].

Pharmacokinetic Analysis

For the analysis of data collected on Day 1 of each period (pre-meal dosing), an analysis of variance (ANOVA) model was used to test the bioequivalence of each of the tested drug formulations. The model included the following factors: treatment, period, sequence, and subject nested within sequence. Ninety percent confidence intervals (CIs) for treatment differences were calculated; the endpoints of these CIs were then reverse transformed to represent CIs about the percent mean ratios on the original scale. With respect to AUC(0-inf) and Cmax, equivalence was declared for each parameter if the bounds of the 90% CIs for the percent mean ratio, comparing a composition according to the invention (Periods 2-12) with Prilosec, were between 80% and 125%.

Determination of Sample Size

A sample size of 12 initial healthy male subjects was considered sufficient to ensure that at least 5 subjects finished the entire trial.

Pharmacokinetic Results

Pharmacokinetic results are presented in Table 13 B. and FIGS. 14-16, 18, 19, 21, 22, 23.

TABLE 13.B Pharmacokinetic Release Profiles of Formulated OME and Prilosec 40 mg Study of Periods 1-12 Intervals (Minutes) ng/mL Period/Test Dosage Day 0 5 10 15 20 30 45 60 Mean Prilosec (P1) 1 0 0 0 0 2 20 205 485 Min Prilosec (P1) 1 0 0 0 0 0 0 37 104 Max Prilosec (P1) 1 0 0 0 0 15 80 543 1474 Mean Capsule (P2) (SAN-10A) 1 0 0 29 176 647 1043 1022 929 Min Capsule (P2) (SAN-10A) 1 0 0 0 0 11 26 152 158 Max Capsule (P2) (SAN-10A) 1 0 0 340 888 1600 2351 2696 2295 Mean Chew Tab (P3) (SAN-15A) 1 0 80 642 921 1001 1092 939 800 Min Chew Tab (P3) (SAN-15A) 1 0 0 73 149 188 177 145 132 Max Chew Tab (P3) (SAN-15A) 1 0 352 1321 1779 2073 2705 2571 2311 Mean Capsule (P4) (SAN-10B) 1 0 0 36 192 413 623 698 682 Min Capsule (P4) (SAN-10B) 1 0 0 0 8 19 94 128 175 Max Capsule (P4) (SAN-10B) 1 0 0 373 966 1403 1727 1801 1792 Mean Chew Tab (P5) (SAN-15B) 1 0 53 473 820 956 958 897 856 Min Chew Tab (P5) (SAN-15B) 1 0 0 36 330 428 379 227 167 Max Chew Tab (P5) (SAN-15B) 1 0 150 1073 1770 2110 2327 2848 3097 Mean Capsule (P6) (SAN-10E) 1 0 0 1 65 502 1007 969 818 Min Capsule (P6) (SAN-10E) 1 0 0 0 0 14 47 156 170 Max Capsule (P6) (SAN-10E) 1 0 0 10 173 1126 2323 2721 2474 Mean Chew Tab (P7) (SAN-15C) 1 0 65 706 1396 1386 1230 1048 852 Min Chew Tab (P7) (SAN-15C) 1 0 0 191 473 711 515 321 226 Max Chew Tab (P7) (SAN-15C) 1 0 382 1172 2807 2306 2580 2358 2117 Mean Capsule (P8) (SAN-10H) 1 0 0 136 293 586 893 848 823 Min Capsule (P8) (SAN-10H) 1 0 0 0 11 57 266 196 197 Max Capsule (P8) (SAN-10H) 1 0 0 451 1100 1428 1697 1627 1871 Mean Capsule (P9) (SAN-10BB) 1 0 0 37 286 867 1198 1111 936 Min Capsule (P9) (SAN-10BB) 1 0 0 0 24 120 299 275 204 Max Capsule (P9) (SAN-10BB) 1 0 0 172 809 1624 2305 1957 2222 Mean Caplet (P10) (SAN-15D) 1 0 56 184 269 199 213 235 322 Min Caplet (P10) (SAN-15D) 1 0 0 5 23 28 49 48 56 Max Caplet (P10) (SAN-15D) 1 0 440 1256 1518 744 595 469 1013 Mean Capsule (P11) (SAN-10C) 1 0 1 33 292 1027 1026 868 767 Min Capsule (P11) (SAN-10C) 1 0 0 0 26 52 267 337 237 Max Capsule (P11) (SAN-10C) 1 0 7 196 827 2024 2056 1729 1992 Mean Caplet (P12) (SAN-15E) 1 0 5 43 81 116 327 540 583 Cmax Tmax ng/mL Period/Test Dosage Day 90 120 180 240 300 360 N (ng/mL) (hr) Mean Prilosec (P1) 1 991 679 417 265 203 143 12 1061 1.38 Min Prilosec (P1) 1 241 127 37 8 8 0 12 273 1.00 Max Prilosec (P1) 1 2994 2146 1596 1093 1081 707 12 2994 1.50 Mean Capsule (P2) (SAN- 1 733 504 309 226 149 107 12 1155 0.76 10A) Min Capsule (P2) (SAN- 1 96 51 19 6 0 0 12 285 0.63 10A) Max Capsule (P2) (SAN- 1 2133 1670 1362 1215 835 676 12 2696 1.50 10A) Mean Chew Tab (P3) (SAN- 1 597 441 280 193 129 95 12 1201 0.54 15A) Min Chew Tab (P3) (SAN- 1 71 42 9 0 0 0 12 196 0.50 15A) Max Chew Tab (P3) (SAN- 1 2133 1701 1322 999 709 587 12 2705 1.50 15A) Mean Capsule (P4) (SAN- 1 799 616 371 274 182 147 12 990 1.22 10B) Min Capsule (P4) (SAN- 1 120 44 9 0 0 0 12 222 0.33 10B) Max Capsule (P4) (SAN- 1 2358 2168 1691 1491 983 900 12 2358 2.00 10B) Mean Chew Tab (P3) (SAN- 1 633 467 305 226 148 122 12 1192 0.50 15C) Min Chew Tab (P3) (SAN- 1 70 29 14 7 0 0 12 428 0.17 15C) Max Chew Tab (P3) (SAN- 1 2586 2058 1532 1279 788 744 12 3097 1.00 15C) Mean Capsule (P6) (SAN-10E) 1 648 436 284 175 137 89 12 1130 0.78 Min Capsule (P6) (SAN-10E) 1 92 51 20 0 0 0 12 399 0.33 Max Capsule (P6) (SAN-10E) 1 2415 1879 1323 994 858 590 12 2721 1.50 Mean Chew Tab (P7) 1 610 436 295 217 161 112 11 1550 0.33 Min Chew Tab (P7) 1 67 31 7 0 0 0 11 711 0.25 Max Chew Tab (P7) 1 2244 1538 1279 1069 760 596 11 2807 0.50 Mean Capsule (P8) (SAN- 1 724 516 323 192 135 102 8 1128 0.78 10H) Min Capsule (P8) (SAN- 1 87 48 14 0 0 0 8 362 0.25 10H) Max Capsule (P8) (SAN- 1 2196 1848 1426 882 685 556 8 2196 1.50 10H) Mean Capsule (P9) (SAN- 1 652 519 323 234 161 118 8 1364 0.55 10BB) Min Capsule (P9) (SAN- 1 120 82 20 0 0 0 8 535 0.33 10BB) Max Capsule (P9) (SAN- 1 1806 1755 1269 1074 824 637 8 2305 0.75 10BB) Mean Caplet (P10) 1 699 598 430 271 178 136 8 111 1.59 Min Caplet (P10) 1 143 97 42 21 10 6 8 531 0.25 Max Caplet (P10) 1 1440 1850 1404 1036 749 633 8 1850 3.00 Mean Capsule (P11) (SAN- 1 591 473 286 204 133 111 7 1378 0.57 10C) Min Capsule (P11) (SAN- 1 74 41 16 0 0 0 7 414 0.33 10C) Max Capsule (P11) (SAN- 1 1842 1826 1214 1004 657 592 7 2056 1.00 10C) Mean Caplet (P12) 1 909 531 320 196 143 110 8 1083 1.59

Formulations in Tables 13A and 13B were prepared according to the following protocols:

Preparation of Capsules

SAN-10A, SAN-10B, SAN-10BB and SAN-10K capsules were prepared on a 1.5 kg batch size in a 6 quart planetary mixer. The grade of each ingredient is shown in Table 13C below. Omeprazole USP is micronized omeprazole obtained from UQUIFA, holder of the Type II DMF for micronized omeprazole.

About half the sodium bicarbonate (#2 USP) was blended together with omeprazole and then with the other half of the sodium bicarbonate. Magnesium hydroxide was screened through a 100 or 60 US mesh screen and then charged into the planetary mixer. Then the entire blend was passed through a #20 mesh s/s screen and reintroduced into the Planetary Mixer and mixed for 10 minutes. Magnesium stearate was screened through a #40 mesh s/s screen directly into the Planetary Mixer and blended for 3 minutes. The mixture was then encapsulated in hard gelatin capsules, size #00, using a Profill® manual encapsulator. The amount of each ingredient used in SAN-10A, SAN-10B, SAN-10BB and SAN-10K capsules is set forth in Table 13C.

Table 13C

SAN-10E and SAN-10H were prepared in a manner similar to that described for SAN-10A, etc., above, except that SAN-10E used a special grade of magnesium hydroxide (MS-95), which is a spray-dried magnesium hydroxide containing 95% magnesium hydroxide and 5% pre-gelatinized starch. SAN-10H is a blend fortified with croscarmellose sodium, which was developed for encapsulation on a Zanasi LZ64 dosator-type encapsulator. The amount of each ingredient is set forth in Table 13C. Both SAN-10E and SAN-10H were encapsulated in hard gelatin capsules, size #00. SAN-10E capsules were encapsulated using the Profill® hand encapsulator. SAN-10H capsules were encapsulated using the Zansi LZ64 dosator type encapsulator. The amount of each ingredient per capsule is set forth in Table 13C below.

Table 13D

Preparation of Chewable Tablets

Micronized omeprazole USP (UQUIFA) was microencapsulated with hydroxypropylcellulose (HPC) using a spray drying process. The grade of HPC was Klucel®, EF. The amount of each excipient used is set forth in Table 13E.

TABLE 13E Weight (%) Feed Weigh (%) Excipient Suspension Dry Product Function Omeprazole USP 6.00% 37.00% API HPC Klucel ® EF, NF 10.0 61.6 Coating Material Sodium Bicarbonate, USP 0.23 1.4 pH Adjuster Purified Water, USP 83.8 N/A Suspension Medium Totals 100.00% 100.00%

HPC was added slowly to purified water and mixed until dissolved. Sodium bicarbonate and omeprazole were then added slowly to prevent agglomeration. The spray composition was then screened prior to introducing it into the spray drier. The spray composition was then spray dried using a Niro® spray drier, which is equipped with a rotary spray atomizer. The final omeprazole content of the microencapsulated formulation is 37%.

Microencapsulated omeprazole was combined with about half the antacid excipient were blended to homogeneity to form an omeprazole pre-blend. The flavor components were next mixed with one another to form a flavor pre-blend. The omeprazole pre-blend and the flavor pre-blend were combined to form a main blend. Finally, a lubricant, magnesium stearate was added to the main blend to form the final blend. Tablets were formed on a commercial Fette press. The amount of the active ingredient and excipients used are set forth in Table 13A, above.

Conclusion

Naked or microencapsulated omeprazole 40 mg in Tablet, Capsule and Caplet forms (Periods 2-12) were bioequivalent to Prilosec® Capsules 40 mg with regard to AUC(0-inf). See FIGS. 14 and 15. The two treatments were not equivalent with regard to peak plasma concentration, Cmax. This difference in Cmax had no apparent effect on the pharmacodynamics or safety of the 40 mg formulation in this trial. The two treatments were also not equivalent with regard to pharmacokinetic release profiles.

Example 14A Formulation of SAN-7F (20 mg Omeprazole Capsules)

A 1300 kg lot of 20 mg omeprazole capsules was manufactured under cGMP conditions. The formulation is set forth in Table 14A, below:

TABLE 14A % Amount Required for Ingredient Weight mg/Capsule 1300 kg Batch (kg) Omeprazole, USP 1.8% 20.4 mg/cap 22.9 kg Sodium 94.8 1100 1232 Bicarbonate, USP #2 Croscarmellose 2.6 30 33.6 Sodium, NF Magnesium 0.9 10 11.2 Stearate, NF Totals 100 1160.4 1300

The following ingredients were added to a tote (tote #1) in the following order: Sodium bicarbonate (about 25% of total), omeprazole USP, sodium bicarbonate (about 25% of total). The contents of tote #1 were then charged into a 60 ft³ V-blender through a Comil® powder mill equipped with a 16 mesh equivalent screen, operating the powder screen at a speed setting of high (800 rpm). The contents were mixed for 5 minutes at 8 rpm. About 25% of the total amount of sodium bicarbonate was then charged into a tote (tote #2). Then the contents of the V-blender were charged into tote #2. The contents of tote #2 were then passed through a Comil® powder mill equipped with a 16 mesh equivalent screen at a speed setting of high (800 rpm).

Next, croscarmellose sodium and the remaining amount of sodium bicarbonate were charged into tote #1. The contents of tote #1 were then passed through a Comil® powder mill equipped with a 16 mesh equivalent screen at a speed setting of high (800 rpm) and charged into the V-blender. The mixture was then blended for 15 minutes a 8 rpm. Then magnesium stearate was screened through a #30 mesh hand screen and charged into the V-blender. The resulting mixture was then blended for 3 minutes at 8 rpm. The contents of the V-blender were then discharged into labeled containers lined with inner clear polyethylene bag overwrapped with an outer black polyethylene bag. The resulting mixture was encapsulated on a H&K 1200® dosing disc/tamping pin-type encapsulator using hard gelatin capsules size #00. Critical Encapsulation Process Parameters

-   -   Encapsulator powder bed depth     -   Dosing disc size     -   Tamping pin settings

The encapsulator powder bed depth, dosing disc size, and tamping pin settings are all controlling factors in achieving target capsule weights and maintaining the consistency of those weights throughout the encapsulation process. The encapsulator powder bed depth is maintained at a uniform level above the dosing disc. The dosing disc size is fixed by the dosing disc thickness, which is 24 mm for the SAN-7F Capsules 20 mg process. Tamping pin settings are adjusted to achieve the desired target weight and maintain consistent weight uniformity.

Example 14B Clinical Trial with SAN-7F 20 mg Capsule Trial Objectives Primary Objective

The primary objective was to test the hypothesis that SAN-7F Capsules 20 mg (omeprazole 20 mg/dose) are pharmacokinetically bioequivalent to Prilosec 20 mg with respect to area under the curve (AUC).

Secondary Objectives:

The secondary objectives were:

1. To assess whether SAN-7F Capsules 20 mg are pharmacodynamically bioequivalent to Prilosec 20 mg with respect to percent decrease from Baseline in integrated gastric acidity; and

2. To compare the pharmacokinetics of SAN-7F Capsules 20 mg administered post-meal to the pharmacokinetics of SAN-7F Capsules 20 mg administered pre-meal.

Design:

This was an open-label, randomized, 2-period crossover trial to evaluate the pharmacokinetics, pharmacodynamics, and safety of 7 consecutive daily doses of SAN-7F. Capsules containing 20 mg omeprazole were compared to 7 consecutive daily doses of Prilosec 20 mg in healthy subjects. A comparison of pharmacokinetic parameters for SAN-7F administered before versus after a meal was conducted.

Volunteers were screened within 21 days before baseline measurements (gastric pH, vital signs). Gastric pH was recorded for 24 hours before the first dose of trial drug. In Period 1, subjects received SAN-7F 20 mg or Prilosec 20 mg, as randomized, 1 hour before breakfast for 7 consecutive days. A standardized high-fat breakfast was given in the clinic 1 hour after dosing on Days 1 and 7, or 1 hour after water for baseline assessment. Standardized lunch and dinner were also given 5 and 10 hours post-dose at baseline and on Days 1 and 7 in the clinic. Blood samples for determination of plasma omeprazole concentrations were collected for 12 hours, and gastric pH was measured for 24 hours after the doses on Days 1 and 7. Subjects who had received SAN-7F 20 mg (omeprazole) in Period 1 were given an eighth dose (Day 8) 1 hour after the start of the standardized high-fat breakfast. Blood samples were collected for 12 hours after the eighth dose (see Section 9.8 regarding the Dose 8 deviation). After a 10- to 14-day washout period, subjects returned for Period 2 and received an alternate treatment from that received in Period 1. Procedures in Period 2 were identical to those in Period 1, except that there was no eighth dose of SAN-7F 20 mg.

Number of Subjects (Planned and Analyzed)

Thirty-six subjects were dosed and 30 subjects complete 7 days of dosing in each period of the trial. Thirty subjects were included in the pharmacokinetic analysis and 25 subjects were included in the pharmacodynamic analysis for Doses 1 and 7. Because of an error in post-meal administration of SAN-7F Capsules 20 mg on Day 8 (Period 1), pharmacokinetic analyses for post-meal administration of SAN-7F Capsules 20 mg were not completed.

Duration of Treatment

Including screening, subjects participated in this trial for up to 40 days.

Design Rationale:

A 2-period crossover design is consistent with FDA guidance for the assessment of comparative pharmacokinetics in healthy volunteers.

Data from 24 subjects were expected to provide adequate power to show bioequivalence between the 2 formulations evaluated in this trial, based on the intersubject variability with regard to the pharmacokinetics [AUC(0-inf)] and pharmacodynamics of omeprazole in previous trials.

The 20-mg dose was studied in support of using a SAN-7F Capsules 20 mg omeprazole dose for short-term treatment of active duodenal ulcer, treatment of heartburn and other symptoms associated with gastroesophageal reflux disease (GERD), short-term treatment of erosive esophagitis, and maintenance of healing of erosive esophagitis.

The primary analysis focused on Day 7 of dosing, since the pharmacokinetics of omeprazole are known to change with repeated dosing and the pharmacodynamic effects are maximal by the seventh day of consecutive daily dosing (steady state).

The time of drug administration (after an overnight fast and 1 hour prior to a meal) meets the regulatory guidance for bioequivalence (fasting) and anticipates actual use.

In Period 1 at steady state (Day 8), the pharmacokinetics of SAN-7F Capsules 20 mg given post-meal were compared to those of SAN-7F 20 mg given pre-meal (Day 7). This comparison was conducted to evaluate the effect of food on the bioavailability of SAN-7F Capsules 20 mg. This portion of the protocol was not conducted correctly during this period.

Treatments Administered:

The treatments administered to subjects in this trial are listed in the table below.

TABLE 14B Treatment Description Treatment Treatment Description SAN-7F SAN-7F Capsules (omeprazole immediate- release capsules) 20 mg administered orally with 120 mL water each morning after an overnight fast, 1 hour before starting a standardized high fat breakfast. Prilosec Prilosec Capsules (omeprazole delayed-release capsules) 20 mg administered orally with 120 mL water each morning after an overnight fast, 1 hour before starting a standardized high-fat breakfast. SAN-7F Dose 8 SAN-7F Capsules (omeprazole immediate- release capsules) 20 mg, administered orally with 120 mL water on Day 8 in Period 1, 1 hour after starting a standardized high-fat breakfast.

The description below represents the schedule of events:

Events:

1. Period 1-SAN-7F Capsules 20 mg or Prilosec 20 mg (by randomization). Location of the lower esophageal sphincter (LES) on the day the subject checked into the clinic (Day minus 2).

Seven consecutive single daily AM doses pre-meal (plus Dose 8 on Day 8 post-meal only for subjects receiving SAN-7F Capsules 20 mg). Twelve-hour PK sampling after Doses 1, 7, and 8 (SAN-7F Capsules 20 mg only). Twenty-four-hour gastric pH monitoring during Baseline starting on Day minus 1, and during treatment starting on Day 1 (Dose 1) and Day 7 (Dose 7).

2. 10-14 Day Washout

3. Period 2—SAN-7F Capsules 20 mg or Prilosec 20 mg—Alternative formulation to that in Period 1. Seven consecutive single daily AM doses pre-meal. Twelve-hour PK sampling after Doses 1 and 7. Twenty-four-hour gastric pH monitoring during Baseline starting on Day minus 1, and during treatment starting on Day 1 (Dose 1) and Day 7 (Dose 7).

Pharmacokinetic Sampling, Analytical Methods, and Parameters

Blood samples (3 mL) were obtained by venipuncture within 30 minutes before each dose and at 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, 360, 420, 480, 540, 600, 660, and 720 minutes (12 hours) after each dose on Days 1 and 7 of both periods and Day 8 of Period 1 (for SAN-7F Capsules 20 mg). Zero time was the time that the subject swallowed a capsule of trial drug.

Plasma omeprazole concentrations were measured using a validated liquid chromatography mass spectrometry (LC-MSIMS) assay (MDS Pharma Services, Lincoln, Nebr.). The linear assay range was 5.0 to 750 ng/mL.

The following pharmacokinetic parameters were measured for each subject:

-   -   Plasma omeprazole concentration at each sampling time     -   Peak omeprazole plasma concentration (Cmax) and the time at         which Cmax is observed (Tmax) obtained directly from the data         without interpolation     -   Terminal elimination rate constant (Kel) determined from a         log-linear regression analysis of the terminal plasma omeprazole         concentrations     -   Half-life of drug elimination (T %) calculated as 0.693/Kel     -   Area under the plasma drug time-concentration curve calculated         from 0 time to last time point evaluated [AUC(0-t)] calculated         using the trapezoidal rule with the plasma concentration at time         t being the last measurable concentration     -   Area under the plasma drug time-concentration curve calculated         from 0 time and extrapolated to infinity [AUC(0-inf)] calculated         as AUC(0-t)+Ct/Kel, where Ct is the last measurable plasma         concentration and Kel is the terminal elimination rate constant         defined above

Measurement of Gastric pH

Subjects remained propped up in bed (about 45 degrees) from the time of initial gastric pH recording, through 5 hours post dose. Subjects were then allowed restricted physical activity until bedtime, at which time they were again propped up in bed (approximately 45 degrees) and remained in this position for the remainder of the pH monitoring period. Gastric pH data were collected every 4 seconds (this measured value was then imputed for each of the following 3 seconds by the software) using an ambulatory pH recording system (Digitrapper@400, Medtronic Functional Diagnostics, Inc, Shoreview, Minn. USA) with a disposable antimony electrode and an internal standard (Medtronic Zinetics 24@ Single-Use pH Catheter with or without the lower esophageal [LES] locator). At the Period 1 check-in (Day minus 2), the LES was located manometrically (Medtronic Polygram '98 for Windows v. 2.20) and the distance from the upper border of the LES to the nares was recorded on the CRF.

For all measurements of gastric pH, the electrode was placed in the stomach 10 cm below the upper border of the LES using measurements determined at Day minus 2 of Period 1. The probe was inserted approximately 1 hour prior to dosing and the proximal end was taped to the side of the face to prevent shifting of the probe. Prior to insertion, the electrode was calibrated at room temperature to pH 1 and 7 using standard commercial polyelectrolyte solutions (Medtronic, Toronto). The software used to process the pH data corrected for the difference between electrode calibration temperature (approximately 25° C.) and recording temperature (37° C.). Recordings continued from approximately 1 minute before until 24 hours after dosing (trial drug or water during Baseline). Times for the following events were indicated electronically on the pH record using the following event markers: beginning of pH recording, dosing of trial drugs, initiation of each meal, and the end of the pH recording.

Readjustment of the gastric pH probe for any potential migration of the pH probe out of the stomach during evening hours was achieved using the following procedures: During baseline periods before dosing, the Digitrappers were checked every hour from 16 hours to 24 hours after administering 120 mL water. If a pH value was >2.5 (1-minute observation), the subject was repositioned and asked to take 1 or more sips of water (≤60 mL total). If the pH did not decrease to ≤2.5 within 5 minutes, the probe was partially withdrawn and then advanced to 10 cm below the upper border of the LES (the administration of ≤60 mL water per hour was permitted to facilitate this procedure). If after repositioning the probe, the pH was not ≤2.5, no further adjustments were made during that hour. These procedures were repeated as necessary during the subsequent hours to ensure that the probe was properly placed. The number of times that the probe was adjusted (water administered or probe repositioned) was recorded on the CRF.

For all dosing periods, the Digitrappers were checked every hour from 16 hours to 24 hours after administering the dose. If the pH was >5 (1-minute observation), the subject was repositioned. If the pH did not decrease to ≤5 within the next 5 minutes, the subject was administered ≤60 ml of water. If the pH did not decrease to ≤5 within the next 1 minute, the probe was partially withdrawn and then advanced to 10 cm below the upper border of the LES (≤60 mL of water may have been administered to facilitate this procedure). If after repositioning the probe, the pH was still >5, no further adjustments were made during that hour. These procedures were repeated, as needed, during the subsequent hour(s) to assure that the probe was properly placed. The hourly assessments and actions taken were recorded on the CRF.

Pharmacodynamic Parameters and Methodology

The following pharmacodynamic parameters were measured for each 24-hour period in 15-minute intervals:

-   -   Integrated gastric acidity (mmol*hr/L), calculated for each         15-minute interval during the 24-hour recording period, as         follows:     -   Acid concentration (mmol/L)=1000×10^(−pH)     -   Acidity (mmol*hr/L)=(acid concentration at time “t” +acid         concentration at time “t₁”)/2×(t-t₁), where t and t₁ are the         times of 2 consecutive pH measurements     -   Integrated gastric acidity (mmol*hr/L) calculated as the sum of         acidity over each 15-minute interval     -   Mean gastric acid concentration (mmol/t), calculated as         integrated gastric acidity for each 15-minute interval/0.25 hour     -   Median gastric pH, calculated for each 15-minute interval     -   Percent time gastric pH was ≤4, calculated for each 15-minute         interval

Values for gastric pH were recorded once every 4 seconds. The software used to process the record filled in the same value for the following 3 seconds. Each record was divided into 15-minute intervals beginning with zero time as the recording interval prior to dosing. All pH values outside the acceptable range of 0.5 to 7.5, inclusive, were excluded prior to analysis.

Missing (or excluded) values for gastric pH were handled as follows:

If pH values were missing in a 15-minute interval, integrated gastric acidity and mean gastric acid concentration were calculated by integrating across the missing data; however, only the available values were used to calculate the percentage of time gastric pH was ≤4 and the median gastric pH.

If all of the pH values were missing in an entire 15 minute interval, integrated gastric acidity, mean gastric acid concentration, and percentage of time gastric pH was ≤4 were calculated as the mean of the values from the interval immediately preceding and immediately following the interval for which all pH values were missing. For an interval with all missing pH values, the median of all values from the interval immediately preceding and immediately following were assigned to the interval with all missing values.

Primary Endpoint

The primary pharmacokinetic endpoint was the bioavailability of omeprazole [AUC(0-inf)] after the seventh dose of each omeprazole formulation.

Secondary Endpoints

The secondary endpoints were:

-   -   Peak plasma concentration (Cmax) after the seventh dose of each         omeprazole formulation.     -   AUC(0-inf) and Cmax after the first dose of each omeprazole         formulation.     -   All other pharmacokinetic parameters after the first and seventh         doses of each omeprazole formulation: Tmax, Kel, T_(1/2),         AUC(0-t).     -   All pharmacokinetic parameters obtained with SAN-7F Capsules 20         mg administered post-meal.

Pharmacokinetic Analysis

For the analysis of data collected on Days 1 and 7 of each period (pre-meal dosing), an analysis of variance (ANOVA) model was used to test the bioequivalence of SAN-7F Capsules 20 mg and Prilosec, using the natural logarithmic transformation of AUC(0-inf) and Cmax. The model included the following factors: treatment, period, sequence, and subject nested within sequence. Ninety percent confidence intervals (CIs) for treatment differences were calculated; the endpoints of these CIs were then reverse transformed to represent CIs about the percent mean ratios on the original scale. With respect to AUC(0-inf) and Cmax, equivalence was declared for each parameter, if the bounds of the 90% CIs for the percent mean ratio, SAN-7F to Prilosec, were between 80% and 125%.

Pharmacodynamic Statistical and Analytical Plan Pharmacodynamic Endpoints Primary Endpoint

The primary pharmacodynamic endpoint was the percent decrease from Baseline in integrated gastric acidity for the 24-hour interval after the seventh dose of each omeprazole formulation.

Secondary Endpoint

The secondary pharmacodynamic endpoint was the percent decrease from Baseline in integrated gastric acidity for the 24-hour interval after the first dose of each omeprazole formulation.

Other Pharmacodynamic Parameters (24-Hour Post-Dose Intervals)

-   -   Mean gastric acid concentration (mM)     -   Median gastric pH     -   Percent time gastric pH

Pharmacodynamic Analysis

The pharmacodynamic effects of SAN-7F Capsules 20 mg and Prilosec 20 mg during the 24-hour post-dose recording period were assessed after the first and seventh doses by evaluating the following parameters: integrated gastric acidity, mean gastric acid concentration, median gastric pH, and the percentage of time gastric pH was ≤4 for the 24-hour period.

Evaluation of Period Effect

Prior to evaluating the pharmacodynamic effects of SAN-7F Capsules and Prilosec with respect to integrated gastric acidity, the possibility of a period effect was assessed using an ANOVA model that included factors for period and subject, fit to the 24-hour baseline values for integrated gastric acidity for each of the 2 periods. If no statistically significant difference was found between the 2 baseline values, it was concluded that there was no period effect. In this case, the mean of the 2 baseline values was used as the baseline value for each subject. If a statistically significant difference was found between the baseline values, it would be concluded that there was a period effect. In this case, integrated gastric acidity was adjusted for the period effect in the statistical analysis by analyzing the percent decrease from the corresponding baseline value for each subject.

Analysis of Pharmacodynamic Endpoints

The analysis of integrated gastric acidity for the 24-hour period following dosing was conducted on the percent decrease from Baseline on Days 1 and 7 calculated for each subject as 100×[Baseline−Day 1 (or Day 7)]/Baseline.

An ANOVA model was used to test the pharmacodynamic equivalence of SAN-7F. Capsules and Prilosec, using the natural logarithmic transformation of percent decrease from Baseline in integrated gastric acidity. The model included the following factors: treatment, period, sequence, and subject nested within sequence. Ninety percent confidence intervals (CIs) for treatment differences were calculated; the endpoints of these CIs were then reverse transformed to represent CIs about the percent mean ratios on the original scale. Pharmacodynamic equivalence was declared if the bounds of the 90% CIs for the percent mean ratio of percent decrease from Baseline in integrated gastric acidity, SAN-7F to Prilosec, were between 80% and 125%.

Descriptive Analyses

The ratio of the percent decrease from Baseline for integrated gastric acidity for the 24-hour period following the first and seventh doses with SAN-7F Capsules and Prilosec was calculated for each subject as: percent decrease from Baseline for SAN-7F/percent decrease from Baseline for Prilosec using the appropriate baseline value. The medians and boundaries of the inter-quartile range (25th and 75th percentiles) of the ratios for all subjects were tabulated.

Analyses of Other Pharmacodynamic Parameters

The ratio of the percent decrease from Baseline for mean gastric acid concentration and for the percentage of time gastric pH was ≤4 for the 24 hour period following dosing with SAN-7F Capsules and Prilosec was calculated for each subject as: percent decrease from Baseline for SAN-7F/percent decrease from Baseline for Prilosec (using the appropriate baseline value). For median gastric pH, the ratio of the increase from Baseline for SAN-7F and Prilosec was calculated for each subject (using the appropriate baseline value) as: increase from Baseline for SAN-7F/increase from Baseline for Prilosec. The medians and boundaries of the inter-quartile range (25th and 75th percentiles) of the ratios for all subjects were tabulated.

Disposition of Subjects

Thirty-six subjects entered the trial and received at least one dose of trial drug; 30 subjects completed the trial.

TABLE 14.C Summary of Subject Disposition n % Subjects who received at least one dose of either trial 36 100.0 drug Subjects who completed both 7-day treatment 30 83.3 periods Subjects who received 8 doses of SAN-7F 20 mg* 22 61.1 Subjects who withdrew 6 16.7 *Includes 15 subjects who received an eighth dose of SAN-7F 20 mg on Day 9 but no dose on Day 8 in Period 1 and 7 other subjects who received 8 consecutive daily dose of SAN-7F 20 mg in Period 2.

Pharmacokinetic Results

Pharmacokinetic results are presented the in Table 14.D. and FIGS. 16, 17, 19, 20, 22 and 23.

After one dose, SAN-7F Capsules 20 mg and Prilosec 20 mg were bioequivalent with respect to AUC. The percent mean ratio of SAN-7F 20 mg to Prilosec 20 mg was 105.31% for AUC(0-inf) with the bounds of the 90% CI between 80% and 125% (98.94% and 112.09%). As expected for the immediate-release product, the Cmax for SAN-7F 20 mg was higher than for Prilosec 20 mg (percent mean ratio of 148.49%, 90% CI of 129.16% to 170.72%). The Tmax for SAN-7F was shorter than the Tmax for Prilosec (p<0.001; ANOVA).

Pharmacokinetic Conclusions

After the first dose and at steady state (Day 7), SAN-7F Capsules 20 mg were equivalent to Prilosec 20 mg with respect to [AUC(0-inf)] (the primary pharmacokinetic endpoint). The 2 treatments were not equivalent with respect to Cmax on Days 1 and 7 with the percent mean ratio of 148% on Day 1 and 145% on Day 7. The Tmax was shorter for the immediate-release product on Days 1 and 7 (p<0.001).

Pharmacodynamic Conclusions

On Day 7 of dosing, SAN-7F Capsules 20 mg were found equivalent to Prilosec 20 mg with regard to the primary pharmacodynamic endpoint, percent decrease from Baseline in integrated gastric acidity over 24 hours. SAN-7F 20 mg and Prilosec 20 mg both decreased integrated gastric acidity by approximately 70% from Baseline at Day 7.

Trial Conclusion

Since comparisons in this trial involved a delayed-release formulation (Prilosec 20 mg) and an immediate-release formulation (SAN-7F Capsules 20 mg), it was anticipated that the Tmax would occur earlier and the Cmax would be higher for SAN-7F 20 mg than for Prilosec 20 mg. It was also expected that the 2 products would be equivalent with regard to AUC and, therefore, also with regard to their pharmacodynamic effects.

As anticipated, SAN-7F 20 mg was found equivalent to Prilosec 20 mg on Day 7 (and Day 1) of dosing with regard to AUC (0-inf) and equivalent at Day 7 with regard to percent decrease from Baseline in integrated gastric acidity over 24 hours. For Cmax, the upper bound of the 90% confidence interval for the percent mean ratio exceeded 125% on Days 1 and 7. The pharmacodynamic data show that SAN-7F 20 mg and Prilosec 20 mg were equally effective in decreasing integrated gastric acidity at steady state (Day 7).

Both SAN-7F Capsules 20 mg and Prilosec 20 mg were well tolerated during the 7-day to 9-day dosing periods in this trial. No meaningful differences between the treatments were observed with respect to safety.

TABLE 14.D 20 mg PK Summary for Day 1 and 7 (S7F = SAN-7F; Pr = Prilosec ®) ng Intervals (minutes) Drug mL Day 0 5 10 15 20 30 45 60 90 120 150 180 S7F Mean 1 0 0 11 111 202 388 320 274 177 83 55 35 S7F Min 1 0 0 0 0 0 0 0 94 36 0 9 0 S7F Max 1 0 0 110 1090 927 1090 958 775 466 246 181 120 S7F Mean 7 0 4 23 125 231 418 417 384 391 245 169 123 S7F Min 7 0 0 0 0 0 0 0 7 22 53 28 15 S7F Max 7 0 120 257 721 1130 1530 1240 1080 1270 735 576 473 Pr Mean 1 0 0 0 0 1 17 87 171 309 160 96 68 Pr Min 1 0 0 0 0 0 0 0 0 81 50 23 13 Pr Max 1 0 0 0 0 27 205 319 441 794 622 394 301 Pr Mean 7 0 0 0 1 8 76 222 292 380 277 194 145 Pr Min 7 0 0 0 0 0 0 0 0 0 62 43 25 Pr Max 7 12 8 8 12 88 333 994 988 1220 775 560 420 20 mg PK Summary for Day 1 and 7 (Continued) (S7F = SAN-7F; Pr = Prilosec ®, 40 mg). Cmax Tmax Drug ng/mL Day 210 240 300 360 420 480 540 600 660 720 N (ng/mL) (hr) S7F Mean 1 22 14 6 3 1 0 0 0 0 0 30 498 0.61 S7F Min 1 0 0 0 0 0 0 0 0 0 0 30 140 0.25 S7F Max 1 76 46 23 18 10 14 0 5 7 6 30 1090 1.50 S7F Mean 7 90 65 38 22 13 7 4 3 1 1 30 680 0.82 S7F Min 7 10 6 0 0 0 0 0 0 0 0 30 228 0.25 S7F Max 7 362 297 196 143 91 61 42 28 18 13 30 1530 1.50 Pr Mean 1 44 28 12 6 3 1 0 0 0 0 30 328 1.41 Pr Min 1 8 0 0 0 0 0 0 0 0 0 30 101 0.75 Pr Max 1 163 105 51 25 13 8 0 0 6 5 30 794 3.00 Pr Mean 7 104 86 47 26 15 8 5 3 1 1 30 487 1.30 Pr Min 7 14 0 0 0 0 0 0 0 0 0 30 170 0.50 Pr Max 7 308 456 167 122 73 65 39 25 18 11 30 1220 2.50

Example 15A Formulation of SAN-7E (40 mg Omeprazole Capsules)

A 1300 kg lot of 40 mg omeprazole capsules was manufactured under cGMP conditions. The formulation is set forth in Table 15A, below:

TABLE 15A % Amount Required for Ingredient Weight mg/Capsule 1300 kg Batch (kg) Omeprazole, USP 3.5% 40.8 mg/cap 45.7 kg Sodium 93.2 1100 1232 Bicarbonate, USP #2 Croscarmellose 1.5 30 33.6 Sodium, NF Magnesium 0.8 10 11.2 Stearate, NF Totals 100 1160.4 1300

The following ingredients were added to a tote (tote #1) in the following order: Sodium bicarbonate (about 25% of total), omeprazole USP, sodium bicarbonate (about 25% of total). The contents of tote #1 were then charged into a 60 ft³ V-blender through a Comil® powder mill equipped with a 16 mesh equivalent screen, operating the powder screen at a speed setting of high (800 rpm). The contents were mixed for 5 minutes at 8 rpm. About 25% of the total amount of sodium bicarbonate was then charged into a tote (tote #2). Then the contents of the V-blender were charged into tote #2. The contents of tote #2 were then passed through a Comil® powder mill equipped with a 16 mesh equivalent screen at a speed setting of high (800 rpm).

Next, croscarmellose sodium and the remaining amount of sodium bicarbonate were charged into tote #1. The contents of tote #1 were then passed through a Comil® powder mill equipped with a 16 mesh equivalent screen at a speed setting of high (800 rpm) and charged into the V-blender. The mixture was then blended for 15 minutes a 8 rpm. Then magnesium stearate was screened through a #30 mesh hand screen and charged into the V-blender. The resulting mixture was then blended for 3 minutes at 8 rpm. The contents of the V-blender were then discharged into labeled containers lined with inner clear polyethylene bag overwrapped with an outer black polyethylene bag. The resulting mixture was encapsulated on a H&K 1200® dosing disc/tamping pin-type encapsulator using hard gelatin capsules size #00.

Example 15B Clinical Trial

A clinical trial was conducted in order to compare the pharmacokinetic profile of a 40 mg omeprazole capsule according to the present invention with Prilosec® 40 mg delayed release capsules. SAN-7E 40 mg capsules according to the invention were formulated as in Example 7B, above. The results of these clinical trials are discussed below and are depicted graphically in FIGS. 16, 18, 19, 21, 22 and 23.

Trial objectives, design, pharmacokinetic and pharmacodynamic endpoints, design rationale, treatments administered, schedule of events, pharmacokinetic sampling, analytical methods and parameters, measurement of gastric pH, pharmacodynamic parameters and methodology, pharmacokinetic statistical and analytical plan are the same as in Example 14 above with the exception of use with SAN-7E Capsules 40 mg and Prilosec 40 mg instead of 20 mg of each drug. The capsules are prepared by blending the PPI and homogeneously blending with other components shown in Table 15A.

Number of Subjects (Planned and Analyzed):

Thirty-six subjects were dosed and 30 subjects complete 7 days of dosing in each period of the trial. Thirty-five subjects were included in the pharmacokinetic analysis and 34 subjects were included in the pharmacodynamic analysis for Doses 1 and 7. Eighteen subjects were included in the post-meal (Day 8) versus pre-meal (Day 7) analysis.

Duration of Treatment:

Including screening, subjects participated in this trial for up to 41 days.

Pharmacokinetic Results

Pharmacokinetic results are presented in the Table 15.B. and FIGS. 16, 18, 19, 21, 22 and 23.

Pharmacokinetic Conclusions

After the first dose and at steady state (Day 7), SAN-7E Capsules 40 mg were equivalent to Prilosec 40 mg with respect to [AUC(0-inf)] (the primary pharmacokinetic endpoint). The 2 treatments were not equivalent with respect to Cmax on Days 1 and 7 with the percent mean ratio of 149% on Day 1 and 117% on Day 7. The Tmax was shorter for the immediate-release product on Days 1 and 7 (p<0.001).

Pharmacodynamic Conclusions

On Day 7 of dosing, SAN-7E Capsules 40 mg were found equivalent to Prilosec 40 mg with regard to the primary pharmacodynamic endpoint, percent decrease from baseline in integrated gastric acidity over 24 hours. SAN-7E 40 mg and Prilosec 40 mg both decreased integrated gastric acidity by 74% and 80%, respectively, from Baseline at Day 7.

TABLE 15.A SAN-7E Capsules Composition, 40 mg Omeprazole Quantity Ingredient (40 mg) Omeprazole  40.8 mg* Sodium Bicarbonate 1100 mg CROSCARMELLOSE SODIUM  30 mg Magnesium Stearate  10 mg Gelatin Capsule   1 shell Total Weight/Unit 1180 mg *Includes a 2% omeprazole overage in the blend manufacture that assures label claim amount of omeprazole in the final product.

TABLE 15.B 40 mg PK Summary for Day 1 and 7. (Drug: S7E = SAN-7E; Pr = Prilosec ® 40 mg.) Interval (minutes) Drug ng/mL Day 0 5 10 15 20 30 45 60 90 120 150 180 S7E Mean 1 0 0 46 237 535 842 840 709 545 338 248 193 S7E Min 1 0 0 0 0 0 24 116 127 0 19 14 7 S7E Max 1 0 12 703 1730 2310 2420 2420 2120 2000 1570 1450 1210 S7E Mean 7 3 3 63 202 398 949 1115 1104 1083 747 585 463 S7E Min 7 0 0 0 0 0 13 32 37 262 0 74 42 S7E Max 7 96 82 1900 3420 2960 3020 2420 2380 2350 1980 1850 1620 Pr Mean 1 0 0 0 0 3 71 195 408 793 546 369 259 Pr Min 1 0 0 0 0 0 0 0 0 111 59 23 10 Pr Max 1 0 0 0 0 58 1800 1140 1580 2650 2100 1650 1350 Pr Mean 7 1 1 1 2 20 171 456 639 1217 969 725 606 Pr Min 7 0 0 0 0 0 0 0 0 12 119 116 67 Pr Max 7 16 14 14 19 392 1420 2110 2230 2950 2370 1770 1620 Cmax Tmax Drug ng/mL Day 210 240 300 360 420 480 540 600 660 720 N (ng/mL) (hr) S7E Mean 1 152 125 86 60 41 30 22 16 12 9 35 1154 0.56 S7E Min 1 5 0 0 0 0 0 0 0 0 0 35 255 0.25 S7E Max 1 1140 1080 871 707 520 457 362 294 230 186 35 2420 1.50 S7E Mean 7 393 323 249 183 131 94 74 53 37 28 35 1526 0.97 S7E Min 7 27 14 0 0 0 0 0 0 0 0 35 437 0.25 S7E Max 7 1570 1570 1350 1190 1060 736 636 572 418 386 35 3420 3.50 Pr Mean 1 208 164 114 77 45 38 27 20 17 12 35 888 1.51 Pr Min 1 0 6 0 0 0 0 0 0 0 0 35 119 0.50 Pr Max 1 1250 1140 919 592 295 422 310 270 217 174 35 2650 2.50 Pr Mean 7 466 397 264 188 131 95 65 46 34 22 35 1344 1.51 Pr Min 7 30 20 7 0 0 00 0 0 0 0 35 234 0.50 Pr Max 7 1420 1260 1000 801 549 435 310 240 199 133 35 2950 2.50 The number of patients who completed the post-meal portion of the study was 18. The following table summarizes the pharmacokinetic parameters for the pre- and post-meal dosing of 40 mg omeprazole immediate release capsules.

TABLE 15.C Summary of Post-meal (Day 8) and Pre-meal (Day 7) Plasma Omeprazole Pharmacokinetic Parameters for Immediate Release Capsules (SAN-7E) Plasma Omeprazole SAN-7E SAN-7E (Post-meal) (Pre-meal) Parameter n Mean S.D. n Mean S.D. Cmax (ng/mL) 18 1026 645.6 18 1646 771.4 Tmax (hr) 18 1.74 1.27 18 0.93 0.74 AUC (0-t)(ng*hr/mL) 18 3221 2349 18 3976 2592 AUC(0-inf)(ng*hr/mL) 18 3221 2488 18 4071 2721 T1/2 (hr) 18 1.38 0.66 18 1.38 0.66 kel (1/hr) 18 0.61 0.26 18 0.61 0.27 In (Cmax) 18 6.70 0.79 18 7.28 0.54 In[AUC(0-t)] 18 7.76 0.90 18 8.01 0.84 IN[AUC(0-inf)] 18 7.78 0.91 18 8.03 0.85

Example 16 Powder for Suspension

Following procedures similar to those set forth in Examples 14 and 15, above, 20 and 40 mg omeprazole immediate release powders for suspension were prepared and tested in subjects. The powder compositions tested are set forth in the following tables 16A and 16B.

TABLE 16A Omeprazole Powder for Suspension 20 mg per dose Omeprazole Immediate Release Powder Ingredient 20 mg per dose Omeprazole, Micronized USP 0.021 Sodium Bicarbonate 1.680 Xanthan Gum 0.039 Sucrose 2.000 Xylitol 2.000 Crystalline Sucralose 0.080 Peppermint Flavor, Mane F94249 0.011 Peach flavor #57.695/AP 05.51 0.030 Totals 5.861

TABLE 16B Omeprazole Powder for Suspension 40 mg per dose Omeprazole Immediate Release Powder Ingredient 40 mg per dose Omeprazole, Micronized USP 0.042 Sodium Bicarbonate 1.680 Xanthan Gum 0.039 Sucrose 2.000 Xylitol 2.000 Crystalline Sucralose 0.080 Peppermint Flavor, Mane F94249 0.011 Peach flavor #57.695/AP 05.51 0.030 Totals 5.882

The results of these clinical trials are set forth in FIGS. 16-23.

Many modifications, equivalents, and variations of the present invention are possible in light of the above teachings, therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced other than as specifically described. 

1-34. (canceled)
 35. A pharmaceutical formulation in a capsule dosage form, comprising: a. about 20 mg of omeprazole or a salt thereof; b. about 1100 mg of sodium bicarbonate; c. croscarmellose sodium; and d. magnesium stearate.
 36. The pharmaceutical formulation of claim 35, further comprising polysorbate-80.
 37. The pharmaceutical formulation of claim 35, wherein the croscarmellose sodium is provided in an amount of about 2 wt-% to about 8 wt-%.
 38. The pharmaceutical formulation of claim 35, wherein the magnesium stearate is provided in an amount of about 0.5 wt-% to about 3 wt-%.
 39. The pharmaceutical formulation of claim 35, further comprising gelatin.
 40. The pharmaceutical formulation of claim 35, wherein the omeprazole is micronized omeprazole. 